Alkyloxy Substituted Thiazoloquinolines and Thiazolonaphthyridines

ABSTRACT

Thiazoloquinolines and thiazolonaphthyridines with an alkoxy substituent at the 6, 7, 8, or 9-position, pharmaceutical compositions containing the compounds, intermediates, methods of making and methods of use of these compounds as immunomodulators, for inducing cytokine biosynthesis in animals and in the treatment of diseases including viral and neoplastic diseases are disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

The present invention claims priority to U.S. Provisional ApplicationSer. No. 60/651,585, filed Feb. 9, 2005, and U.S. ProvisionalApplication Ser. No. 60/733,036, filed Nov. 3, 2005, both of which areincorporated herein by reference.

BACKGROUND

Certain compounds have been found to be useful as immune responsemodifiers (IRMs), rendering them useful in the treatment of a variety ofdisorders. However, there continues to be interest in and a need forcompounds that have the ability to modulate the immune response, byinduction of cytokine biosynthesis or other mechanisms.

SUMMARY

The present invention provides a new class of compounds that are usefulin inducing cytokine biosynthesis in animals. Such compounds are of thefollowing Formula I:

wherein R_(A), R_(B), and R″ are as defined below.

The compounds of Formula I are useful as immune response modifiers dueto their ability to induce cytokine biosynthesis (e.g., induces thesynthesis of at least one cytokine) and otherwise modulate the immuneresponse when administered to animals. This makes the compounds usefulin the treatment of a variety of conditions such as viral diseases andtumors that are responsive to such changes in the immune response.

The invention further provides pharmaceutical compositions containing aneffective amount of a compound of Formula I and methods of inducingcytokine biosynthesis in an animal, treating a viral infection ordisease and/or treating a neoplastic disease in an animal byadministering an effective amount of a compound of Formula I to theanimal.

In addition, methods of synthesizing compounds of Formula I andintermediates useful in the synthesis of these compounds are provided.

As used herein, “a”, “an”, “the”, “at least one”, and “one or more” areused interchangeably.

The terms “comprises” and variations thereof do not have a limitingmeaning where these terms appear in the description and claims.

The above summary of the present invention is not intended to describeeach disclosed embodiment or every implementation of the presentinvention. The description that follows more particularly exemplifiesillustrative embodiments. In several places throughout the description,guidance is provided through lists of examples, which examples can beused in various combinations. In each instance, the recited list servesonly as a representative group and should not be interpreted as anexclusive list.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS OF THE INVENTION

The present invention provides compounds of the following Formulas Ithrough VII:

as well as intermediates of the following Formulas X through XIII:

wherein R_(A), R_(B), R″, R, R₂, R₃, n, G, and Z are as defined below.

In one embodiment, the present invention provides a compound of FormulaI:

wherein:

R_(A) and R_(B) taken together form a fused benzene ring or fusedpyridine ring wherein the benzene ring or pyridine ring is substitutedby one —O—R₃ group, or substituted by one —O—R₃ group and one R group;

R₃ is selected from the group consisting of:

-   -   -Z-Y—R₄,    -   -Z-Y—X—Y—R₄,    -   -Z-Y-x-Y—X—Y—R₄,    -   -Z-R₅,    -   -Z-Het,    -   -Z-Het′-R₄, and    -   -Z-Het′-Y—R₄;

R is selected from the group consisting of alkyl, alkoxy, hydroxy,halogen, and trifluoromethyl;

R″ is hydrogen or a non-interfering substituent;

Z is selected from the group consisting of alkylene, alkenylene, andalkynylene, wherein alkylene, alkenylene, and alkynylene can beoptionally interrupted with one or more —O— groups;

Y is selected from the group consisting of:

-   -   —S(O)₀₋₂—,    -   —S(O)₂—N(R₉)—,    -   —C(R₆)—,    -   —C(R₆)—O—,    -   —O—C(R₆)—,    -   —O —C(O)—O—,    -   —N(R₈)-Q-,    -   —C(R₆)—N(R₈)—,    -   —O—C(R₆)—N(R₈)—,    -   —C(R₆)—N(OR₉)—,    -   —O—N(R₈)-Q-,    -   —O—N═C(R₄)—,    -   —C(═N—O—R₈)—,    -   —CH(—N(—O—R₈)-Q-R₄)—,

Het is heterocyclyl which can be unsubstituted or substituted by one ormore substituents independently selected from the group consisting ofalkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy,hydroxyalkyl, cyano, hydroxyalkyleneoxyalkylenyl, amino, alkylamino,dialkylamino, and oxo;

Het′ is heterocyclylene which can be unsubstituted or substituted by oneor more substituents independently selected from the group consisting ofalkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy,hydroxyalkyl, cyano, amino, alkylamino, dialkylamino, and oxo;

X is selected from the group consisting of alkylene, alkenylene,alkynylene, arylene, heteroarylene, and heterocyclylene wherein thealkylene, alkenylene, and alkynylene groups can be optionallyinterrupted or terminated with arylene, heteroarylene, orheterocyclylene, and optionally interrupted by one or more —O— groups;

R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, diallylamino,(diallylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo;

R₅ is selected from the group consisting of:

R₆ is selected from the group consisting of ═O and ═S;

R₇ is C₂₋₇ alkylene;

R₈ is selected from the group consisting of hydrogen, alkyl,hydroxyalkylenyl, alkoxyalkylenyl, arylalkylenyl, andheteroarylalkylenyl;

R₉ is selected from the group consisting of hydrogen and alkyl;

R₁₀ is C₃₋₈ alkylene;

A is selected from the group consisting of —O—, —CH₂—, —C(O)—,—S(O)₀₋₂—, and —N(R₄)—;

A′ is selected from the group consisting of —O—, —S(O)O₀₋₂—, —N(-Q-R₄)—,and —CH₂—;

Q is selected from the group consisting of a bond, —C(R₆)—,—C(R₆)—C(R₆)—, —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, and—C(R₆)—N(OR₉)—;

V is selected from the group consisting of —C(R₆)—, —O—C(R₆)—,—N(R₈)—C(R₆)—, and —S(O)₂—;

W is selected from the group consisting of a bond, —C(O)—, and —S(O)₂—;and

a and b are independently integers from 1 to 6 with the proviso that a+bis ≦7;

with the proviso that Z can also be a bond when:

-   -   R₃ is -Z-Het, -Z-Het′-R₄, or -Z-Het′-Y—R₄, and Z is attached to        an atom other than N in Het or Het′; or    -   R₃ is -Z-Y—R₄, -Z-Y—X—Y—R₄, or -Z-Y—X—Y—X—Y—R₄, and the Y group        bonded to Z is —S(O)₂—, —S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—,        —C(R₆)—N(R₈)—,

wherein V is —C(R₆)— or —S(O)₂—, or

or

-   -   R₃ is -Z-R₅, and R₅ is

wherein V is —C(R₆)— or —S(O)₂—, or

and

with the further proviso that Y can also be —O— when:

-   -   Y is bonded to R₄, and R₄ is selected from the group consisting        of hydrogen, aryl, and heteroaryl, wherein aryl and heteroaryl        can be unsubstituted or substituted by one or more substituents;        or    -   Y is bonded to Z and X, and X is arylene or heteroarylene;        or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides a compound of FormulaII:

wherein:

R₃ is selected from the group consisting of:

-   -   -Z-Y—R₄,    -   -Z-Y—X—Y—R₄,    -   -Z-Y—X—Y—X—Y—R₄,    -   -Z-R₅,

-Z-Het,

-   -   -Z-Het′-R₄, and    -   -Z-Het′-Y—R₄;

R is selected from the group consisting of alkyl, alkoxy, hydroxy,halogen, and trifluoromethyl;

n is 0 or 1;

R₂ is selected from the group consisting of:

-   -   —R₄,    -   —X—R₄,    -   —X—Y′—R₄, and    -   —X—R₅′;

Z is selected from the group consisting of alkylene, alkenylene, andalkynylene, wherein alkylene, alkenylene, and alkynylene can beoptionally interrupted with one or more —O— groups;

Y is selected from the group consisting of:

-   -   —S(O)₀₋₂—,    -   —S(O)₂—N(R₈)—,    -   —C(R₆)—,    -   —C(R₆)—O—,    -   —O—C(R₆)—,    -   —O—C(O)—O—,    -   —N(R₈)-Q-,    -   —C(R₆)—N(R₈)—,    -   —O—C(R₆)—N(R₈)—,    -   —C(R₆)—N(OR₉)—,    -   —O—N(R₈)-Q-,    -   —O—N═C(R₄)—,    -   —C(═N—O—R₈)—,    -   —CH(—N(—O—R₈)-Q-R₄)—,

Het is heterocyclyl which can be unsubstituted or substituted by one ormore substituents independently selected from the group consisting ofalkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy,hydroxyalkyl, cyano, hydroxyalkyleneoxyalkylenyl, amino, alkylamino,dialkylamino, and oxo;

Het′ is heterocyclylene which can be unsubstituted or substituted by oneor more substituents independently selected from the group consisting ofalkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy,hydroxyalkyl, cyano, amino, alkylamino, dialkylamino, and oxo;

X is selected from the group consisting of alkylene, alkenylene,alkynylene, arylene, heteroarylene, and heterocyclylene wherein thealkylene, alkenylene, and alkynylene groups can be optionallyinterrupted or terminated with arylene, heteroarylene, orheterocyclylene, and optionally interrupted by one or more —O— groups;

Y′ is selected from the group consisting of:

-   -   —O—,    -   —S(O)₀₋₂—,    -   —S(O)₂—N(R₈)—,    -   —C(R₆)—,    -   —C(R₆)—O—,    -   —O—C(R₆)—,    -   —O—C(O)—O—,    -   —N(R₈)-Q-,    -   —C(R₆)—N(R₈)—,    -   —O—C(R₆)—N(R₈)—,    -   —C(R₆)—N(OR₉)—,

R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo;

R₅ is selected from the group consisting of:

R₅′ is selected from the group consisting of:

R₆ is selected from the group consisting of ═O and ═S;

R₇ is C₂₋₇ alkylene;

R₈ is selected from the group consisting of hydrogen, alkyl,hydroxyalkylenyl, alkoxyalkylenyl, arylalkylenyl, andheteroarylalkylenyl;

R₉ is selected from the group consisting of hydrogen and alkyl;

R₁₀ is C₃₋₈ alkylene;

A is selected from the group consisting of —O—, —CH₂—, —C(O)—,—S(O)₀₋₂—, and —N(R₄)—;

A′ is selected from the group consisting of —O—, —S(O)₀₋₂—, —N(-Q-R₄)—,and —CH₂—;

Q is selected from the group consisting of a bond, —C(R₆)—,—C(R₆)—C(R₆)—, —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, and—C(R₆)—N(OR₉)—;

V is selected from the group consisting of-C(R₆)—, —O—C(R₆)—,—N(R₈)—C(R₆)—, and —S(O)₂—;

W is selected from the group consisting of a bond, —C(O)—, and —S(O)₂—;and

a and b are independently integers from 1 to 6 with the proviso that a+bis ≦7;

with the proviso that Z can also be a bond when:

-   -   R₃ is -Z-Het, -Z-Het′-R₄, or -Z-Het′-Y—R₄, and Z is attached to        an atom other than N in Het or Het′; or    -   R₃ is -Z-Y—R₄, -Z-Y—X—Y—R₄, or -Z-Y—X—Y—X—Y—R₄, and the Y group        bonded to Z is —S(O)₂—, —S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—,        —C(R₆)—N(R₈)—,

wherein V is —C(R₆)— or —S(O)₂—, or

or

-   -   R₃ is -Z-R₅, and R₅ is

wherein V is —C(R₆)— or —S(O)₂—,or

and

with the further proviso that Y can also be —O— when:

-   -   Y is bonded to R₄, and R₄ is selected from the group consisting        of hydrogen, aryl, and heteroaryl, wherein aryl and heteroaryl        can be unsubstituted or substituted by one or more substituents;        or    -   Y is bonded to Z and X, and X is arylene or heteroarylene;        or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides a compound selectedfrom the group consisting Formulas III, IV, V, and VI:

wherein:

R₃ is selected from the group consisting of:

-   -   -Z-Y—R₄,    -   -Z-Y—X—Y—R₄,    -   -Z-Y—X—Y—X—Y—R₄,    -   -Z-R₅,    -   -Z-Het,    -   -Z-Het′-R₄, and    -   -Z-Het′-Y—R₄;

R is selected from the group consisting of alkyl, alkoxy, hydroxy,halogen, and trifluoromethyl;

n is 0 or 1;

R₂ is selected from the group consisting of:

-   -   —R₄,    -   —X—R₄,    -   —X—Y′—R₄, and    -   —X—R₅′;

Z is selected from the group consisting of alkylene, alkenylene, andalkynylene, wherein alkylene, alkenylene, and alkynylene can beoptionally interrupted with one or more —O— groups;

Y is selected from the group consisting of:

-   -   —S(O)₀₋₂—,    -   —S(O)₂—N(R₈)—,    -   —C(R₆)—,    -   —C(R₆)—O—,    -   —O—C(R₆)—,    -   —O—C(O)—O—,    -   —N(R₈)-Q-,    -   —C(R₆)—N(R₈)—,    -   —O—C(R₆)—N(R₈)—,    -   —C(R₆)—N(OR₉)—,    -   O—N(R₈)-Q-,    -   —O—N═C(R₄)—,    -   —C(═N—O—R₈)—,    -   —CH(—N(—O—R₈)-Q-R₄)—,

Het is heterocyclyl which can be unsubstituted or substituted by one ormore substituents independently selected from the group consisting ofalkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy,hydroxyalkyl, cyano, hydroxyalkyleneoxyalkylenyl, amino, alkylamino,dialkylamino, and oxo;

Het′ is heterocyclylene which can be unsubstituted or substituted by oneor more substituents independently selected from the group consisting ofalkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy,hydroxyalkyl, cyano, amino, alkylamino, dialkylamino, and oxo;

X is selected from the group consisting of alkylene, alkenylene,alkynylene, arylene, heteroarylene, and heterocyclylene wherein thealkylene, alkenylene, and alkynylene groups can be optionallyinterrupted or terminated with arylene, heteroarylene, orheterocyclylene, and optionally interrupted by one or more —O— groups;

Y′ is selected from the group consisting of:

-   -   —O—,    -   —S(O)₀₋₂—,    -   —S(O)₂—N(R₈)—,    -   —C(R₆)—,    -   —C(R₆)—O—,    -   —O—C(R₆)—,    -   —O—C(O)—O—,    -   —N(R₈)-Q-,    -   —C(R₆)—N(R₈)—,    -   —O—C(R₆)—N(R₈)—,    -   —C(R₆)—N(OR₉)—,

R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo;

R₅ is selected from the group consisting of:

R₅′ is selected from the group consisting of:

R₆ is selected from the group consisting of ═O and ═S;

R₇ is C₂₋₇ alkylene;

R₈ is selected from the group consisting of hydrogen, alkyl,hydroxyalkylenyl, alkoxyalkylenyl, arylalkylenyl, andheteroarylalkylenyl;

R₉ is selected from the group consisting of hydrogen and alkyl;

R₁₀ is C₃₋₈ alkylene;

A is selected from the group consisting of —O—, —CH₂—, —C(O)—,—S(O)₀₋₂—, and —N(R₄)—;

A′ is selected from the group consisting of —O—, —S(O)₀₋₂—, —N(-Q-R₄)—,and —CH₂—;

Q is selected from the group consisting of a bond, —C(R₆)—,—C(R₆)—C(R₆)—, —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, and—C(R₆)—N(OR₉)—;

V is selected from the group consisting of —C(R₆)—, —O—C(R₆)—,—N(R₈)—C(R₆)—, and —S(O)₂—;

W is selected from the group consisting of a bond, —C(O)—, and —S(O)₂—;and

a and b are independently integers from 1 to 6 with the proviso that a+bis ≦7;

with the proviso that Z can also be a bond when:

-   -   R₃ is -Z-Het, -Z-Het′-R₄, or -Z-Het′-Y—R₄, and Z is attached to        an atom other than N in Het or Het′; or    -   R₃ is -Z-Y—R₄, -Z-Y—X—Y—R₄, or -Z-Y—X—Y—X—Y—R₄, and the Y group        bonded to Z is —S(O)₂—, —S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—,        —C(R₆)—N(R₈)—,

wherein V is —C(R₆)— or —S(O)₂—, or

or

-   -   R₃ is -Z-R₅, and R₅ is

wherein V is —C(R₆)— or —S(O)₂—, or

and

with the further proviso that Y can also be —O— when:

-   -   Y is bonded to R₄, and R₄ is selected from the group consisting        of hydrogen, aryl, and heteroaryl, wherein aryl and heteroaryl        can be unsubstituted or substituted by one or more substituents;        or    -   Y is bonded to Z and X, and X is arylene or heteroarylene; or a        pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides a compound (which is aprodrug) of Formula VII:

wherein:

R_(A) and R_(B) taken together form a fused benzene ring or fusedpyridine ring wherein the benzene ring or pyridine ring is substitutedby one —O—R₃ group, or substituted by one —O—R₃ group and one R group;

R₃ is selected from the group consisting of:

-   -   -Z-Y—R₄,    -   -Z-Y—X—Y—R₄,    -   -Z-Y—X—Y—X—Y—R₄,    -   -Z-R₅,    -   -Z-Het,    -   -Z-Het′-R₄, and    -   -Z-Het′-Y—R₄;

R is selected from the group consisting of alkyl, alkoxy, hydroxy,halogen, and trifluoromethyl;

G is selected from the group consisting of:

-   -   —C(O)—R′,    -   α-aminoacyl,    -   α-aminoacyl-α-aminoacyl,    -   —C(O)—O—R′,    -   —C(O)—N(R′″)R′,    -   C(—NY₁)—R′,    -   —CH(OH)—C(O)—OY₁,    -   —CH(OC₁₋₄ alkyl)Y₀,    -   —CH₂Y₂, and    -   —CH(CH₃)Y₂;

R′ and R′″ are independently selected from the group consisting of C₁₋₁₀alkyl, C₃₋₇ cycloalkyl, phenyl, and benzyl, each of which may beunsubstituted or substituted by one or more substituents independentlyselected from the group consisting of halogen, hydroxy, nitro, cyano,carboxy, C₁₋₆ alkyl, C₁₋₄ alkoxy, aryl, heteroaryl, aryl-C₁₋₄ alkylenyl,heteroaryl-C₁₋₄ alkylenyl, halo-C₁₋₄ alkylenyl, halo-C₁₋₄ alkoxy,—O—C(O)—CH₃, —C(O)—O—CH₃, —C(O)—NH₂, —O—CH₂—C(O)—NH₂, —NH₂, and—S(O)₂—NH₂, with the proviso that R′″ can also be hydrogen;

α-aminoacyl is an α-aminoacyl group derived from an amino acid selectedfrom the group consisting of racemic, D-, and L-amino acids;

Y₁ is selected from the group consisting of hydrogen, C₁₋₆ alkyl, andbenzyl;

Y₀ is selected from the group consisting of C₁₋₆ alkyl, carboxy-C₁₋₆alkylenyl, amino-C₁₋₄ alkylenyl, mono-N—C₁₋₆ alkylamino-C₁₋₄ alkylenyl,and di-N,N—C₁₋₆ alkylamino-C₁₋₄ alkylenyl;

Y₂ is selected from the group consisting of mono-N—C₁₋₆ alkylamino,di-N,N—C₁₋₆ alkylamino, morpholin-4-yl, piperidin-1-yl, pyrrolidin-1-yl,and 4-C₁₋₄ alkylpiperazin-1-yl;

R₂ is selected from the group consisting of:

-   -   —R₄,    -   —X—R₄,    -   —X—Y′—R₄, and    -   —X—R₅′;

Z is selected from the group consisting of alkylene, alkenylene, andalkynylene, wherein alkylene, alkenylene, and alkynylene can beoptionally interrupted with one or more —O— groups;

Y is selected from the group consisting of:

-   -   —S(O)₀₋₂—,    -   —S(O)₂—N(R₈)—,    -   —C(R₆)—,    -   —C(R₆)—O—,    -   —O—C(R₆)—,    -   —O—C(O)—O—,    -   —N(R₈)-Q-,    -   —C(R₆)—N(R₈)—,    -   —O—C(R₆)—N(R₈)—,    -   —C(R₆)—N(OR₉)—,    -   —O—N(R₈)-Q-,    -   —O—N═C(R₄)—,    -   —C(═N—O—R₈)—,    -   —CH(—N(—O—R₈)-Q-R₄)—,

Het is heterocyclyl which can be unsubstituted or substituted by one ormore substituents independently selected from the group consisting ofalkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy,hydroxyalkyl, cyano, hydroxyalkyleneoxyalkylenyl, amino, alkylamino,dialkylamino, and oxo;

Het′ is heterocyclylene which can be unsubstituted or substituted by oneor more substituents independently selected from the group consisting ofalkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy,hydroxyalkyl, cyano, amino, alkylamino, dialkylamino, and oxo;

X is selected from the group consisting of alkylene, alkenylene,alkynylene, arylene, heteroarylene, and heterocyclylene wherein thealkylene, alkenylene, and alkynylene groups can be optionallyinterrupted or terminated with arylene, heteroarylene, orheterocyclylene, and optionally interrupted by one or more —O— groups;

Y′ is selected from the group consisting of:

-   -   —O—,    -   —S(O)₀₋₂—,    -   —S(O)₂—N(R₈)—,    -   —C(R₆)—,    -   —C(R₆)—O—,    -   —O—C(R₆)—,    -   —O—C(O)—O—,    -   —N(R₈)-Q-,    -   —C(R₆)—N(R₈)—,    -   —O—C(R₆)—N(R₈)—,    -   —C(R₆)—N(OR₉)—,

R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo;

R₅ is selected from the group consisting of:

R₅′ is selected from the group consisting of:

R₆ is selected from the group consisting of ═O and ═S;

R₇ is C₂₋₇ alkylene;

R₈ is selected from the group consisting of hydrogen, alkyl,hydroxyalkylenyl, alkoxyalkylenyl, arylalkylenyl, andheteroarylalkylenyl;

R₉ is selected from the group consisting of hydrogen and alkyl;

R₁₀ is C₃₋₈ alkylene;

A is selected from the group consisting of —O—, —CH₂—, —C(O)—,—S(O)₀₋₂—, and —N(R₄)—;

A′ is selected from the group consisting of —O—, —S(O)O₀₋₂—, —N(-Q-R₄)—,and —CH₂—;

Q is selected from the group consisting of a bond, —C(R₆)—,—C(R₆)—C(R₆)—, —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, and—C(R₆)—N(OR₉)—;

V is selected from the group consisting of-C(R₆)—, —O—C(R₆)—,—N(R₈)—C(R₆)—, and —S(O)₂—;

W is selected from the group consisting of a bond, —C(O)—, and —S(O)₂—;and

a and b are independently integers from 1 to 6 with the proviso that a+bis ≦7;

with the proviso that Z can also be a bond when:

-   -   R₃ is -Z-Het, -Z-Het′-R₄, or -Z-Het′-Y—R₄, and Z is attached to        an atom other than N in Het or Het′; or    -   R₃ is -Z-Y—R₄, -Z-Y—X—Y—R₄, or -Z-Y—X—Y—X—Y—R₄, and the Y group        bonded to Z is —S(O)₂—, —S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—,        —C(R₆)—N(R₈)—,

wherein V is —C(R₆)— or —S(O)₂—, or

or

-   -   R₃ is -Z-R₅, and R₅ is

wherein V is —C(R₆)— or —S(O)₂—, or

and

with the further proviso that Y can also be —O— when:

-   -   Y is bonded to R₄, and R₄ is selected from the group consisting        of hydrogen, aryl, and heteroaryl, wherein aryl and heteroaryl        can be unsubstituted or substituted by one or more substituents;        or    -   Y is bonded to Z and X, and X is arylene or heteroarylene;        or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides an intermediatecompound of Formula X, which is also an IRM:

wherein:

R is selected from the group consisting of alkyl, alkoxy, hydroxy,halogen, and trifluoromethyl;

n is 0 or 1;

R₂ is selected from the group consisting of:

-   -   —R₄,    -   —X—R₄,    -   —X—Y′—R₄, and    -   —X—R₅′;

Z is selected from the group consisting of alkylene, alkenylene, andalkynylene, wherein alkylene, alkenylene, and alkynylene can beoptionally interrupted with one or more —O— groups;

X is selected from the group consisting of alkylene, alkenylene,alkynylene, arylene, heteroarylene, and heterocyclylene wherein thealkylene, alkenylene, and alkynylene groups can be optionallyinterrupted or terminated with arylene, heteroarylene, orheterocyclylene, and optionally interrupted by one or more —O— groups;

Y′ is selected from the group consisting of:

-   -   —O—,    -   —S(O)₀₋₂—,    -   —S(O)₂—N(R₈)—,    -   —C(R₆)—,    -   —C(R₆)—O—,    -   —O—C(R₆)—,    -   —O—C(O)—O—,    -   —N(R₈)-Q-,    -   —C(R₆)—N(R₈)—,    -   —O—C(R₆)—N(R₉)—,    -   —C(R₆)—N(OR₉)—,

R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo;

R₅′ is selected from the group consisting of:

R₆ is selected from the group consisting of ═O and ═S;

R₇ is C₂₋₇ alkylene;

R₈ is selected from the group consisting of hydrogen, alkyl,hydroxyalkylenyl, alkoxyalkylenyl, arylalkylenyl, andheteroarylalkylenyl;

R₉ is selected from the group consisting of hydrogen and alkyl;

R₁₀ is C₃₋₈ alkylene;

A is selected from the group consisting of —O—, —CH₂—, —C(O)—,—S(O)₀₋₂—, and —N(R₄)—;

Q is selected from the group consisting of a bond, —C(R₆)—,—C(R₆)—C(R₆)—, —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, and—C(R₆)—N(OR₉)—;

V is selected from the group consisting of-C(R₆)—, —O—C(R₆)—,—N(R₈)—C(R₆)—, and —S(O)₂—;

W is selected from the group consisting of a bond, —C(O)—, and —S(O)₂—;and

a and b are independently integers from 1 to 6 with the proviso that a+bis ≦7;

or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides an intermediatecompound of Formula XI, which is also an IRM:

wherein:

R is selected from the group consisting of alkyl, alkoxy, hydroxy,halogen, and trifluoromethyl;

n is 0 or 1;

R₂ is selected from the group consisting of:

-   -   —R₄,    -   —X—R₄,    -   —X—Y′—R₄, and    -   —X—R₅′;

Z is selected from the group consisting of alkylene, alkenylene, andalkynylene, wherein alkylene, alkenylene, and alkynylene can beoptionally interrupted with one or more —O— groups;

X is selected from the group consisting of alkylene, alkenylene,alkynylene, arylene, heteroarylene, and heterocyclylene wherein thealkylene, alkenylene, and alkynylene groups can be optionallyinterrupted or terminated with arylene, heteroarylene, orheterocyclylene, and optionally interrupted by one or more —O— groups;

Y′ is selected from the group consisting of:

-   -   —O—,    -   —S(O)₀₋₂—,    -   —S(O)₂—N(R₈)—,    -   —C(R₆)—,    -   —C(R₆)—O—,    -   —O—C(R₆)—,    -   —O—C(O)—O—,    -   —N(R₈)-Q-,    -   —C(R₆)—N(R₈)—,    -   —O—C(R₆)—N(R₈)—,    -   —C(R₆)—N(OR₉)—,

R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo;

R₅′ is selected from the group consisting of:

R₆ is selected from the group consisting of ═O and ═S;

R₇ is C₂₋₇ alkylene;

R₈ is selected from the group consisting of hydrogen, alkyl,hydroxyalkylenyl, alkoxyalkylenyl, arylalkylenyl, andheteroarylalkylenyl;

R₉ is selected from the group consisting of hydrogen and alkyl;

R₁₀ is C₃₋₈ alkylene;

A is selected from the group consisting of —O—, —CH₂—, —C(O)—,—S(O)₀₋₂—, and —N(R₄)—;

Q is selected from the group consisting of a bond, —C(R₆)—,—C(R₆)—C(R₆)—, —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, and—C(R₆)—N(OR₉)—;

V is selected from the group consisting of-C(R₆)—, —O—C(R₆)—,—N(R₈)—C(R₆)—, and —S(O)₂—;

W is selected from the group consisting of a bond, —C(O)—, and —S(O)₂—;and

a and b are independently integers from 1 to 6 with the proviso that a+bis ≦7;

or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides an intermediatecompound of Formula XII:

wherein:

R₃ is selected from the group consisting of:

-   -   -Z-Y—R₄,    -   -Z-Y—X—Y—R₄,    -   -Z-Y—X—Y—X—Y—R₄,    -   -Z-R₅,    -   -Z-Het,    -   -Z-Het′-R₄, and    -   -Z-Het′-Y—R₄;

R is selected from the group consisting of alkyl, alkoxy, hydroxy,halogen, and trifluoromethyl;

n is 0 or 1;

R₂ is selected from the group consisting of:

-   -   —R₄,    -   —X—R₄,    -   —X—Y′—R₄, and    -   —X—R₅′;

Z is selected from the group consisting of alkylene, alkenylene, andalkynylene, wherein alkylene, alkenylene, and alkynylene can beoptionally interrupted with one or more —O— groups;

Y is selected from the group consisting of:

-   -   —S(O)₀₋₂—,    -   —S(O)₂—N(R₈)—,    -   —C(R₆)—,    -   —C(R₆)—O—,    -   —O—C(R₆)—,    -   —O—C(O)—O—,    -   —N(R₈)-Q-,    -   —C(R₆)—N(R₈)—,    -   —O—C(R₆)—N(R₈)—,    -   —C(R₆)—N(OR₉)—,    -   —O—N(R₈)-Q-,    -   —O—N═C(R₄)—,    -   —C(═N—O—R₈)—,    -   —CH(—N(—O—R₈)-Q-R₄)—,

Het is heterocyclyl which can be unsubstituted or substituted by one ormore substituents independently selected from the group consisting ofalkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy,hydroxyalkyl, cyano, hydroxyalkyleneoxyalkylenyl, amino, alkylamino,dialkylamino, and oxo;

Het′ is heterocyclylene which can be unsubstituted or substituted by oneor more substituents independently selected from the group consisting ofalkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy,hydroxyalkyl, cyano, amino, alkylamino, dialkylamino, and oxo;

X is selected from the group consisting of alkylene, alkenylene,alkynylene, arylene, heteroarylene, and heterocyclylene wherein thealkylene, alkenylene, and alkynylene groups can be optionallyinterrupted or terminated with arylene, heteroarylene, orheterocyclylene, and optionally interrupted by one or more —O— groups;

Y′ is selected from the group consisting of:

-   -   —O—,    -   —S(O)₀₋₂—,    -   —S(O)₂—N(R₉)—,    -   —C(R₆)—,    -   —C(R₆)—O—,    -   —O—C(R₆)—,    -   —O—C(O)—O—,    -   —N(R₈)-Q-,    -   —C(R₆)—N(R₈)—,    -   —O—C(R₆)—N(R₈)—,    -   —C(R₆)—N(OR₉)—,

R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo;

R₅ is selected from the group consisting of:

R₅′ is selected from the group consisting of:

R₆ is selected from the group consisting of ═O and ═S;

R₇ is C₂₋₇ alkylene;

R₈ is selected from the group consisting of hydrogen, alkyl,hydroxyalkylenyl, alkoxyalkylenyl, arylalkylenyl, andheteroarylalkylenyl;

R₉ is selected from the group consisting of hydrogen and alkyl;

R₁₀ is C₃₋₈ alkylene;

A is selected from the group consisting of —O—, —CH₂—, —C(O)—,—S(O)₀₋₂—, and —N(R₄)—;

A′ is selected from the group consisting of —O—, —S(O)₀₋₂—, —N(-Q-R₄)—,and —CH₂—;

Q is selected from the group consisting of a bond, —C(R₆)—,—C(R₆)—C(R₆)—, —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, and—C(R₆)—N(OR₉)—;

V is selected from the group consisting of-C(R₆)—, —O—C(R₆)—,—N(R₈)—C(R₆)—, and —S(O)₂—;

W is selected from the group consisting of a bond, —C(O)—, and —S(O)₂—;and

a and b are independently integers from 1 to 6 with the proviso that a+bis ≦7;

with the proviso that Z can also be a bond when:

-   -   R₃ is -Z-Het, -Z-Het′-R₄, or -Z-Het′-Y—R₄, and Z is attached to        an atom other than N in Het or Het′; or    -   R₃ is -Z-Y—R₄, -Z-Y—X—Y—R₄, or -Z-Y—X—Y—X—Y—R₄, and the Y group        bonded to Z is —S(O)₂—, —S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—,        —C(R₆)—N(R₈)—,

wherein V is —C(R₆)— or —S(O)₂—, or

or

-   -   R₃ is -Z-R₅, and R₅ is

wherein V is —C(R₆)— or —S(O)₂—, or

and

with the further proviso that Y can also be —O— when:

-   -   Y is bonded to R₄, and R₄ is selected from the group consisting        of hydrogen, aryl, and heteroaryl, wherein aryl and heteroaryl        can be unsubstituted or substituted by one or more substituents;        or    -   Y is bonded to Z and X, and X is arylene or heteroarylene;        or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides an intermediatecompound of Formula XIII:

wherein:

R₃ is selected from the group consisting of:

-   -   -Z-Y—R₄,    -   -Z-Y—X—Y—R₄,    -   -Z-Y—X—Y—X—Y—R₄,    -   -Z-R₅,    -   -Z-Het,    -   -Z-Het′-R₄, and    -   -Z-Het′-Y—R₄;

R is selected from the group consisting of alkyl, alkoxy, hydroxy,halogen, and trifluoromethyl;

n is 0or 1;

R₂ is selected from the group consisting of:

-   -   —R₄,    -   —X—R₄,    -   —X—Y′—R₄, and    -   —X—R₅′;

Z is selected from the group consisting of alkylene, alkenylene, andalkynylene, wherein alkylene, alkenylene, and alkynylene can beoptionally interrupted with one or more —O— groups;

Y is selected from the group consisting of:

-   -   —S(O)₀₋₂—,    -   —S(O)₂—N(R₈)—,    -   —C(R₆)—,    -   —C(R₆)—O—,    -   —O—C(R₆)—,    -   —O—C(O)—O—,    -   —N(R₈)-Q-,    -   —C(R₆)—N(R₈)—,    -   —O—C(R₆)—N(R₈)—,    -   —C(R₆)—N(OR₉)—,    -   —O—N(R₈)-Q-,    -   —O—N═C(R₄)—,    -   —C(═N—O—R₈)—,    -   —CH(—N(—O —R₈)-Q-R₄)—,

Het is heterocyclyl which can be unsubstituted or substituted by one ormore substituents independently selected from the group consisting ofalkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy,hydroxyalkyl, cyano, hydroxyalkyleneoxyalkylenyl, amino, alkylamino,dialkylamino, and oxo;

Het′ is heterocyclylene which can be unsubstituted or substituted by oneor more substituents independently selected from the group consisting ofalkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy,hydroxyalkyl, cyano, amino, alkylamino, dialkylamino, and oxo;

X is selected from the group consisting of alkylene, alkenylene,alkynylene, arylene, heteroarylene, and heterocyclylene wherein thealkylene, alkenylene, and alkynylene groups can be optionallyinterrupted or terminated with arylene, heteroarylene, orheterocyclylene, and optionally interrupted by one or more —O— groups;

Y′ is selected from the group consisting of:

-   -   —O—,    -   —S(O)₀₋₂—,    -   —S(O)₂—N(R₈)—,    -   —C(R₆)—,    -   —C(R₆)—O—,    -   —O—C(R₆)—,    -   —O—C(O)—O—,    -   —N(R₈)-Q-,    -   —C(R₆)—N(R₈)—,    -   —O—C(R₆)—N(R₈)—,    -   —C(R₆)—N(OR₉)—,

R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alklylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo;

R₅ is selected from the group consisting of:

R₅′ is selected from the group consisting of:

R₆ is selected from the group consisting of ═O and ═S;

R₇ is C₂₋₇ alkylene;

R₈ is selected from the group consisting of hydrogen, alkyl,hydroxyalkylenyl, alkoxyalkylenyl, arylalkylenyl, andheteroarylalkylenyl;

R₉ is selected from the group consisting of hydrogen and alkyl;

R₁₀ is C₃₋₈ alkylene;

A is selected from the group consisting of —O—, —CH₂—, —C(O)—,—S(O)₀₋₂—, and —N(R₄)—;

A′ is selected from the group consisting of —O—, —S(O)₀₋₂—-, —N(-Q-R₄)—,and —CH₂—;

Q is selected from the group consisting of a bond, —C(R₆)—,—C(R₆)—C(R₆)—, —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, and—C(R₆)—N(OR₉)—;

V is selected from the group consisting of-C(R₆)—, —O—C(R₆)—,—N(R₉)—C(R₆)—, and —S(O)₂—;

W is selected from the group consisting of a bond, —C(O)—, and —S(O)₂—;and

a and b are independently integers from 1 to 6 with the proviso that a+bis ≦7;

with the proviso that Z can also be a bond when:

-   -   R₃ is -Z-Het, -Z-Het′-R₄, or -Z-Het′-Y—R₄, and Z is attached to        an atom other than N in Het or Het′; or    -   R₃ is -Z-Y—R₄, -Z-Y—X—Y—R₄, or -Z-Y—X—Y—X—Y—R₄, and the Y group        bonded to Z is —S(O)₂—, —S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—,        —C(R₆)—N(R₈)—,

wherein V is —C(R₆)— or —S(O)₂—, or

or

-   -   R₃ is -Z-R₅, and R₅ is

wherein V is —C(R₆)— or —S(O)₂—, or

and

with the further proviso that Y can also be —O— when:

-   -   Y is bonded to R₄, and R₄ is selected from the group consisting        of hydrogen, aryl, and heteroaryl, wherein aryl and heteroaryl        can be unsubstituted or substituted by one or more substituents;        or    -   Y is bonded to Z and X, and X is arylene or heteroarylene;        or a pharmaceutically acceptable salt thereof.

Herein, “non-interfering” means that the ability of the compound orsalt, which includes a non-interfering substituent, to modulate thebiosynthesis of one or more cytokines is not destroyed by thenon-interfering substituent. Illustrative non-interfering R″ groupsinclude those described above for R₂.

As used herein, the terms “alkyl”, “alkenyl”, “alkynyl” and the prefix“alk-” are inclusive of both straight chain and branched chain groupsand of cyclic groups, e.g., cycloalkyl and cycloalkenyl. Unlessotherwise specified, these groups contain from 1 to carbon atoms, withalkenyl groups containing from 2 to 20 carbon atoms, and alkynyl groupscontaining from 2 to 20 carbon atoms. In some embodiments, these groupshave a total of up to 10 carbon atoms, up to 8 carbon atoms, up to 6carbon atoms, or up to 4 carbon atoms. Cyclic groups can be monocyclicor polycyclic and preferably have from 3 to 10 ring carbon atoms.Exemplary cyclic groups include cyclopropyl, cyclopropylmethyl,cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl,cyclohexyl, cyclohexylmethyl, adamantyl, and substituted andunsubstituted bornyl, norbornyl, and norbornenyl.

Unless otherwise specified, “alkylene”, “-alkylene-”, “alkenylene”,“-alkenylene-”, “alkynylene”, and “-alkynylene-” are the divalent formsof the “alkyl”, “alkenyl”, and “alkynyl” groups defined above. The terms“alkylenyl”, “alkenylenyl”, and “alkynylenyl” are used when “alkylene”,“alkenylene”, and “alkynylene”, respectively, are substituted. Forexample, an arylalkylenyl group comprises an “alkylene” moiety to whichan aryl group is attached.

The term “haloalkyl” is inclusive of alkyl groups that are substitutedby one or more halogen atoms, including perfluorinated groups. This isalso true of other groups that include the prefix “halo-”. Examples ofsuitable haloalkyl groups are chloromethyl, trifluoromethyl, and thelike.

The term “aryl” as used herein includes carbocyclic aromatic rings orring systems. Examples of aryl groups include phenyl, naphthyl,biphenyl, fluorenyl and indenyl.

Unless otherwise indicated, the term “heteroatom” refers to the atoms O,S, or N.

The term “heteroaryl” includes aromatic rings or ring systems thatcontain at least one ring heteroatom (e.g., O, S, N). In someembodiments, the term “heteroaryl” includes a ring or ring system thatcontains 2 to 12 carbon atoms, 1 to 3 rings, 1 to 4 heteroatoms, and O,S, and/or N as the heteroatoms. Suitable heteroaryl groups includefuryl, thienyl, pyridyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl,triazolyl, pyrrolyl, tetrazolyl, imidazolyl, pyrazolyl, oxazolyl,thiazolyl, benzofuranyl, benzothiophenyl, carbazolyl, benzoxazolyl,pyrimidinyl, benzimidazolyl, quinoxalinyl, benzothiazolyl,naphthyridinyl, isoxazolyl, isothiazolyl, purinyl, quinazolinyl,pyrazinyl, 1-oxidopyridyl, pyridazinyl, triazinyl, tetrazinyl,oxadiazolyl, thiadiazolyl, and so on.

The term “heterocyclyl” includes non-aromatic rings or ring systems thatcontain at least one ring heteroatom (e.g., O, S, N) and includes all ofthe fully saturated and partially unsaturated derivatives of the abovementioned heteroaryl groups. In some embodiments, the term“heterocyclyl” includes a ring or ring system that contains 2 to 12carbon atoms, 1 to 3 rings, 1 to 4 heteroatoms, and O, S, and N as theheteroatoms. Exemplary heterocyclyl groups include pyrrolidinyl,tetrahydrofuranyl, morpholinyl, thiomorpholinyl,1,1-dioxothiomorpholinyl, piperidinyl, piperazinyl, thiazolidinyl,imidazolidinyl, isothiazolidinyl, tetrahydropyranyl, quinuclidinyl,homopiperidinyl (azepanyl), 1,4-oxazepanyl, homopiperazinyl(diazepanyl), 1,3-dioxolanyl, aziridinyl, azetidinyl,dihydroisoquinolin-(1H)-yl, octahydroisoquinolin-(1H)-yl,dihydroquinolin-(2H)-yl, octahydroquinolin-(2H)-yl,dihydro-1H-imidazolyl, 3-azabicyclo[3.2.2]non-3-yl, and the like.

The term “heterocyclyl” includes bicylic and tricyclic heterocyclic ringsystems. Such ring systems include fused and/or bridged rings and spirorings. Fused rings can include, in addition to a saturated or partiallysaturated ring, an aromatic ring, for example, a benzene ring. Spirorings include two rings joined by one spiro atom and three rings joinedby two spiro atoms.

When “heterocyclyl” contains a nitrogen atom, the point of attachment ofthe heterocyclyl group may be the nitrogen atom.

The terms “arylene”, “heteroarylene”, and “heterocyclylene” are thedivalent forms of the “aryl”, “heteroaryl”, and “heterocyclyl” groupsdefined above. The terms, “arylenyl”, “heteroarylenyl”, and“heterocyclylenyl” are used when “arylene”, “heteroarylene,” and“heterocyclylene”, respectively, are substituted. For example, analkylarylenyl group comprises an arylene moiety to which an alkyl groupis attached.

When a group (or substituent or variable) is present more than once inany Formula described herein, each group (or substituent or variable) isindependently selected, whether explicitly stated or not. For example,for the formula —N(R₈)—C(R₆)—N(R₈)— each R₈ group is independentlyselected. In another example, when an R₂ and an R₃ group both contain anR₄ group, each R₄ group is independently selected. In a further example,when more than one Y group is present and each Y group contains one ormore R₈ groups, then each Y group is independently selected, and each R₈group is independently selected.

The invention is inclusive of the compounds described herein (includingintermediates) in any of their pharmaceutically acceptable forms,including isomers (e.g., diastereomers and enantiomers), salts,solvates, polymorphs, prodrugs, and the like. In particular, if acompound is optically active, the invention specifically includes eachof the compound's enantiomers as well as racemic mixtures of theenantiomers. It should be understood that the term “compound” includesany or all of such forms, whether explicitly stated or not (although attimes, “salts” are explicitly stated).

The term “prodrug” means a compound that can be transformed in vivo toyield an immune response modifying compound, including any of the salt,solvated, polymorphic, or isomeric forms described above. The prodrug,itself, may be an immune response modifying compound, including any ofthe salt, solvated, polymorphic, or isomeric forms described above. Thetransformation may occur by various mechanisms, such as through achemical (e.g., solvolysis or hydrolysis, for example, in the blood) orenzymatic biotransformation. A discussion of the use of prodrugs isprovided by T. Higuchi and W. Stella, “Pro-drugs as Novel DeliverySystems,” Vol. 14 of the A. C. S. Symposium Series, and in BioreversibleCarriers in Drug Design, ed. Edward B. Roche, American PharmaceuticalAssociation and Pergamon Press, 1987.

For any of the compounds presented herein, each one of the followingvariables (e.g., Z, X, Y, Y′, R_(A), R_(B), R, R₂, R₃, Q, n, and so on)in any of its embodiments can be combined with any one or more of theother variables in any of their embodiments and associated with any oneof the formulas described herein, as would be understood by one of skillin the art. Each of the resulting combinations of variables is anembodiment of the present invention.

For certain embodiments of Formulas I and VII, particularly embodimentsof Formula I, R_(A) and R_(B) are taken together to form a fused benzenering wherein the benzene ring is substituted by one —O—R₃ group, orsubstituted by one —O—R₃ group and one R group. In certain of theseembodiments, the fused benzene ring is substituted by one —O—R₃ group.

For certain embodiments of Formulas I and VII, particularly embodimentsof Formula I, R_(A) and R_(B) are taken together to form a fusedpyridine ring wherein the pyridine ring is substituted by one —O—R₃group, or substituted by one —O—R₃ group and one R group. In certain ofthese embodiments, the fused pyridine ring is substituted by one —O—R₃group.

For certain embodiments, the compound selected from the group consistingof Formulas III, IV, V, and VI, or a pharmaceutically acceptable saltthereof is the compound of Formula III:

or a pharmaceutically acceptable salt thereof.

For certain embodiments, n is 0 in the above embodiments of Formulas II,III, IV, V, and VI.

For certain embodiments, R is selected from the group consisting ofalkyl, alkoxy, hydroxy, halogen, and trifluoromethyl.

For certain embodiments, R″ is hydrogen or a non-interferingsubstituent.

For certain embodiments, R″ is a non-interfering substituent.

For certain embodiments, R″ is R₂; wherein R₂ is selected from the groupconsisting of —R₄, —X—R₄, —X—Y′—R₄, and —X—R₅′.

For certain embodiments, R₂ is selected from the group consisting of—R₄, —X—R₄, —X—Y′—R₄, and —X—R₅′.

For certain embodiments, including any one of the above embodimentswherein R₂ is present, R₂ is selected from the group consisting ofhydrogen, alkyl, alkoxyalkylenyl, and hydroxyalkylenyl. For certainembodiments, R₂ is selected from the group consisting of hydrogen,alkyl, and alkoxyalkylenyl. For certain embodiments, R₂ is selected fromthe group consisting of alkyl and alkoxyalkylenyl. For certainembodiments, R₂ is selected from the group consisting of hydrogen,methyl, ethyl, propyl, butyl, ethoxymethyl, methoxymethyl,2-methoxyethyl, hydroxymethyl, and 2-hydroxyethyl. For certainembodiments, R₂ is selected from the group consisting of methyl, ethyl,n-propyl, n-butyl, ethoxymethyl, methoxymethyl, and 2-methoxyethyl.

For certain embodiments, particularly embodiments of Formula X, n is 0and R₂ is selected from the group consisting of hydrogen, alkyl,alkoxyalkylenyl, and hydroxyalkylenyl.

For certain embodiments, R₃ is selected from the group consisting of-Z-Y—R₄, -Z-Y—X—Y—R₄, -Z-Y—X—Y—X—Y—R₄, -Z-R₅, -Z-Het, -Z-Het′-R₄, and-Z-Het′-Y—R₄.

For certain embodiments, including any one of the above embodiments, R₃is Z-Y—R₄ or -Z-Y—X—Y—R₄. In certain of these embodiments, Y is—N(R₈)-Q-,

or —C(O)—; wherein Q is selected from the group consisting of a bond,—C(O)—, —C(O)—O—, —S(O)₂—, —C(R₆)—N(R₈)—, and —S(O)₂—N(R₈)—; R₆ isselected from the group consisting of ═O or ═S; R₇ is C₂₋₃ alkylene; R₈is selected from the group consisting of hydrogen, C₁₋₄ alkyl, and C₁₋₄alkoxyC₁₋₄ alkylenyl; R₁₀ is C₃₋₆ alkylene; and R₄ is selected from thegroup consisting of alkyl, aryl, arylalkylenyl, alkylheteroarylenyl,heteroarylalkylenyl, heteroaryl, and heterocyclyl; wherein alkyl isunsubstituted or substituted by one or more substituents selected fromthe group consisting of hydroxy, alkoxy, halogen, and aryl; whereinaryl, heteroaryl, and arylalkylenyl are unsubstituted or substituted byone or more substituents selected from the group consisting of alkyl,halogen, cyano, dialkylamino, and alkoxy; and wherein heterocyclyl isunsubstituted or substituted by one or more alkyl substituents. Incertain other of these embodiments, Y is —N(R₈)-Q- or

wherein Q is selected from the group consisting of a bond, —C(O)—,—C(O)—O—, —S(O)₂—, and —C(R₆)—N(R₈)—; R₆ is selected from the groupconsisting of ═O or ═S; R₇ is C₂₋₃ alkylene; R₈ is selected from thegroup consisting of hydrogen, C₁₋₄ alkyl, and C₁₋₄ alkoxyC₁₋₄ alkylenyl;and R₄ is selected from the group consisting of alkyl, aryl,arylalkylenyl, alkylheteroarylenyl, heteroarylalkylenyl, heteroaryl, andheterocyclyl; wherein alkyl is unsubstituted or substituted by one ormore substituents selected from the group consisting of hydroxy, alkoxy,and aryl; wherein aryl and arylalkylenyl are unsubstituted orsubstituted by one or more substituents selected from the groupconsisting of alkyl, halogen, cyano, dialkylamino, and alkoxy; andwherein heterocyclyl is unsubstituted or substituted by one or morealkyl substituents. In certain of these embodiments, Y is —N(R₈)-Q-. Incertain of these embodiments, Q is —C(O)—. In certain of theseembodiments, Q is —S(O)₂—. In certain of these embodiments, Q is—C(R₆)—N(R₈)—. In certain of these embodiments, 4 is C₁₋₄ alkyl and R₉is hydrogen. In certain other of these embodiments, R₄ is phenyl that isunsubstituted or substituted by methoxy and R₈ is hydrogen. In certainembodiments, Q is a bond. In certain of these embodiments, R₄ isheterocyclyl that is unsubstituted or substituted by one or more alkylgroups, and R₈ is C₁₋₄ alkyl. In certain of these embodiments, R₄ is1-methylpiperidin-4-yl and R₈ is methyl. In certain embodiments, R₃ is-Z-Y—R₄, wherein Y is —O— and R₄ is phenyl that is unsubstituted orsubstituted by one or more substituents selected from the groupconsisting of alkyl, halogen, cyano, alkoxy, nitro, and haloalkyl. Incertain other embodiments, R₃ is -Z-Y—X—Y, —R₄, wherein Y is —O—, X isphenylene, and Y_(c)—R₄ is selected from the group consisting of—C(O)-alkyl, —C(O)—O-alkyl, —S-alkyl, —NH—C(O)-alkyl, —C(O)—NH₂, and—S(O)₂—NH₂.

For certain embodiments, including any one of the above embodiments notexcluding this definition, R₃ is -Z-R₅. In certain of these embodiments,R₅ is selected from the group consisting of:

wherein A is —O—, —CH₂—, or —S(O)₂—; R₇ is C₂₋₄ alkylene; R₈ is hydrogenor C₁₋₄ alkyl; and a and b are each independently 1, 2, or 3. In certainembodiments, R₅ is

wherein R₇ is C₂₋₄ alkylene.

For certain embodiments, including any one of the above embodiments notexcluding this definition, R₃ is -Z-Het or -Z-Het′-R₄. In certain ofthese embodiments, Het and Het′ are, respectively, selected from thegroup consisting of the monovalent and divalent forms oftetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanyl, azetidinyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,1,1-dioxothiomorpholinyl, thiazolidinyl, azepanyl, 1,4-oxazepanyl,diazepanyl, dihydroisoquinolin-(1H)-yl, octahydroisoquinolin-(1H)-yl,dihydroquinolin-(2H)-yl, octahydroquinolin-(2H)-yl,dihydro-1H-imidazolyl, 3-azabicyclo[3.2.2]non-3-yl, and piperazinyl,each of which is unsubstituted or substituted by one or moresubstituents. For certain of these embodiments, Het and Het′ are,respectively, selected from the group consisting of the monovalent anddivalent forms of pyrrolidinyl, piperidinyl, and morpholinyl, each ofwhich is unsubstituted or substituted by one or more substituents. Forcertain of these embodiments, Het is unsubstituted. For certain of theseembodiments, Het′ is unsubstituted. For certain of these embodiments,Het is substituted by one or more substituents selected from the groupconsisting of alkyl, hydroxy, hydroxyalkyl, hydroxyalkyleneoxyalkylenyl,and dialkylamino. For certain of these embodiments, R₄ is heterocyclyl.For certain of these embodiments, R₄ is selected from the groupconsisting of pyrrolidinyl and piperidinyl.

For certain embodiments, including any one of the above embodiments notexcluding this definition, R₃ is -Z-Het′-Y—R₄. In certain of theseembodiments, Het′ is selected from the group consisting of the divalentform of tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl,azepanyl, diazepanyl, dihydroisoquinolin-(1H)-yl,octahydroisoquinolin-(1H)-yl, dihydroquinolin-(2B)-yl,octahydroquinolin-(2H)-yl, dihydro-1H-imidazolyl, and piperazinyl. Incertain of these embodiments, —Y—R₄ is selected from the groupconsisting of —C(O)-alkyl, —C(O)—O—H, —C(O)—O-alkyl, —C(O)—NH₂—,—C(O)—NH-alkyl, and —NH—C(O)-alkyl.

For certain embodiments, R₃ includes a substituted or unsubstitutedthiazolo[4,5-c]quinolinyl group or a substituted or unsubstitutedthiazolo[4,5-c]naphthyridinyl group and a connecting group such that thecompound is a dimer. In certain of these embodiments, R₃ is-Z—Y_(a)—X—Y_(b)—R₄ wherein Y_(a) is —N(R₈)-Q-, Y_(b) is —O—, and R₄ isthiazolo[4,5-c]quinolinyl or thiazolo[4,5-c]naphthyridinyl. In certainof these embodiments, Q is —C(R₆)—N(R₈)—. In certain of theseembodiments, the thiazolo[4,5-c]quinolinyl orthiazolo[4,5-c]naphthyridinyl group is substituted by alkyl and amino.

For certain embodiments, including any one of the above embodiments, Zis alkylene optionally interrupted with one or more —O— groups. Incertain of these embodiments, Z is selected from the group consisting ofC₁₋₆ alkylene and —CH₂CH₂—O—CH₂CH₂—.

For certain embodiments, including any one of the above embodimentspermitted by the proviso for Formulas I through VII, more particularlyfor Formulas I through VI, and which do not exclude this definition, Zis a bond.

For certain embodiments, including any of the above embodiments, —O—R₃is at the 7-position. For other embodiments, —O—R₃ is at the 8-position.

For certain embodiments, R₄ is selected from the group consisting ofhydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkylenyl,aryloxyalkylenyl, alkylarylenyl, heteroaryl, heteroarylalkylenyl,heteroaryloxyalkylenyl, alkylheteroarylenyl, and heterocyclyl whereinthe alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl,alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo.

For certain embodiments, R₄ is selected from the group consisting ofalkyl, aryl, arylalkylenyl, alkylheteroarylenyl, heteroarylalkylenyl,heteroaryl, and heterocyclyl. For certain of these embodiments, alkyl isunsubstituted or substituted by one or more substituents selected fromthe group consisting of hydroxy, alkoxy, and aryl. For certain other ofthese embodiments, alkyl is unsubstituted or substituted by one or moresubstituents selected from the group consisting of hydroxy, alkoxy,halogen, and aryl. For certain of these embodiments, aryl andarylalkylenyl are unsubstituted or substituted by one or moresubstituents selected from the group consisting of alkyl, halogen,cyano, dialkylamino, and alkoxy. For certain of these embodiments, aryl,heteroaryl, and arylalkylenyl are unsubstituted or substituted by one ormore substituents selected from the group consisting of alkyl, halogen,cyano, dialkylamino, and alkoxy. For certain of these embodiments,heterocyclyl is unsubstituted or substituted by one or more alkylsubstituents.

For certain embodiments, R₄ is hydrogen or alkyl.

For certain embodiments, R₄ is alkyl.

For certain embodiments, R₄ is C₁₋₄ alkyl.

For certain embodiments, R₄ is heterocyclyl. For certain of theseembodiments, R₄ is selected from the group consisting of pyrrolidinyland piperidinyl.

For certain embodiments, R₄ is heterocyclyl that is unsubstituted orsubstituted by one or more alkyl groups. For certain of theseembodiments, R₄ is 1-methylpiperidin-4-yl.

For certain embodiments, R₄ is phenyl that is unsubstituted orsubstituted by methoxy.

For certain embodiments, R₄ is heteroaryl.

For certain embodiments, R₄ is phenyl that is unsubstituted orsubstituted by one or more substituents selected from the groupconsisting of alkyl, halogen, cyano, alkoxy, nitro, and haloalkyl.

For certain embodiments, R₅ is selected from the group consisting of:

For certain embodiments, R₅ is selected from the group consisting of:

In certain of these embodiments A is —O—, —CH₂—, or —S(O)₂—; R₇ is C₂₋₄alkylene; R₈ is hydrogen or C₁₋₄ alkyl; and a and b are eachindependently 1, 2, or 3. In certain of these embodiments a and b areeach 2.

For certain embodiments, R₅ is

In certain of these embodiments, R₇ is C₂₋₄ alkylene. For certainembodiments, R₅ is

In certain of these embodiments, R₇ is C₂₋₄ alkylene.

For certain embodiments, R₅′ is selected from the group consisting of:

For certain embodiments, R₆ is selected from the group consisting of ═Oand ═S.

For certain embodiments, R₆ is ═O. For certain embodiments, R₆ is ═S.

For certain embodiments, R₇ is C₂₋₇ alkylene.

For certain embodiments, R₇ is C₂₋₄ alkylene.

For certain embodiments, R₇ is C₂₋₃ alkylene. Preferably, in a ring offormula

R₇ is C₂₋₃ alkylene.

For certain embodiments, R₈ is selected from the group consisting ofhydrogen, alkyl, hydroxyalkylenyl, alkoxyalkylenyl, arylalkylenyl, andheteroarylalkylenyl.

For certain embodiments, R₈ is selected from the group consisting ofhydrogen, C₁₋₄ alkyl, and C₁₋₄ alkoxyC₁₋₄ alkylenyl.

For certain embodiments, R₈ is hydrogen or C₁₋₄ alkyl.

For certain embodiments, R₈ is hydrogen.

For certain embodiments, R₈ is C₁₋₄ alkyl. For certain embodiments, R₈is methyl.

For certain embodiments, R₉ is selected from the group consisting ofhydrogen and alkyl.

For certain embodiments, R₁₀ is C₃₋₈ alkylene.

For certain embodiments, R₁₀ is C₄₋₆ alkylene.

For certain embodiments, R₁₀ is C₃₋₆ alkylene.

For certain embodiments, A is selected from the group consisting of —O—,—CH₂—, —C(O)—, —S(O)₀₋₂—, and —N(R₄)—.

For certain embodiments, A is —O—, —CH₂—, or —S(O)₂—.

For certain embodiments, A is —O— or —S(O)₂—.

For certain embodiments, A is —O—.

For certain embodiments, A′ is selected from the group consisting of—O—, —S(O)₀₋₂—, —N(-Q-R₄)—, and —CH₂—.

In certain embodiments, A′ is selected from the group consisting of—CH₂—, —S(O)₂—, and —O—.

In certain embodiments, A′ is —CH₂—.

In certain embodiments, A′ is —O—.

In certain embodiments, Q is selected from the group consisting of abond, —C(R₆)—, —C(R₆)—C(R₆)—, —S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—,—C(R₆)—O—, and —C(R₆)—N(OR₉)—.

In certain embodiments, Q is selected from the group consisting of abond, —C(O)—, —C(O)—O—, —S(O)₂—, —C(R₆)—N(R₈)—, and —S(O)₂—N(R₈)—.

In certain embodiments, Q is selected from the group consisting of abond, —C(O)—, —C(O)—O—, —S(O)₂—, and —C(R₆)—N(R₈)—.

In certain embodiments, Q is —C(O)—.

In certain embodiments, Q is —S(O)₂—.

In certain embodiments, Q is —C(R₆)—N(R₈)—.

In certain embodiments, Q is a bond.

In certain embodiments, V is selected from the group consisting of—C(R₆)—, —O—C(R₆)—, —N(R₈)—C(R₆)—, and —S(O)₂—.

In certain embodiments, V is selected from the group consisting of—C(O)— and —N(R₈)—C(O)—.

In certain embodiments, W is selected from the group consisting of abond, —C(O)—, and —S(O)₂—.

In certain embodiments, W is a bond or —C(O)—.

In certain embodiments, W is a bond.

In certain embodiments, X is selected from the group consisting ofalkylene, alkenylene, alkynylene, arylene, heteroarylene, andheterocyclylene wherein the alkylene, alkenylene, and alkynylene groupscan be optionally interrupted or terminated with arylene, heteroarylene,or heterocyclylene, and optionally interrupted by one or more —O—groups. For certain embodiments, X is phenylene. For certainembodiments, X is alkylene.

In certain embodiments, Y is selected from the group consisting of —O—,—S(O)₀₋₂—, —S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—, —O—C(R₆)—, —O—C(O)—O—,—N(R₈)-Q-, —C(R₆)—N(R₈)—, —O—C(R₆)—N(R₈)—, —C(R₆)—N(OR₈)—, —O—N(R₈)-Q-,—O—N═C(R₄)—, —C(═N—O—R₈)—,

In certain embodiments, Y is selected from the group consisting of—S(O)₀₋₂—, —S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—, —O—C(R₆)—, —O—C(O)—O—,—N(R₈)-Q-, —C(R₆)—N(R₈)—, —O—C(R₆)—N(R₈)—, —C(R₆)—N(OR₉)—, —O—N(R₈)-Q-,—O—N═C(R₄)—, —C(═N—O—R₈)—, —CH(—N(—O—R₈)-Q-R₄)—,

In certain of these embodiments, Y can also be —O—. For example, Y canalso be —O— when Y is bonded to R₄, and R₄ is selected from the groupconsisting of hydrogen, aryl, and heteroaryl, wherein aryl andheteroaryl can be unsubstituted or substituted by one or moresubstituents. For these embodiments, the one or more substituents areindependently selected from the group consisting of alkyl, alkoxy,hydroxyalkyl, haloalkyl, haloalkoxy, halogen, nitro, hydroxy, mercapto,cyano, aryl, aryloxy, arylalkyleneoxy, heteroaryl, heteroaryloxy,heteroarylalkyleneoxy, heterocyclyl, amino, alkylamino, dialkylamino,and (dialkylamino)alkyleneoxy. In another example, Y can also be —O—when Y is bonded to Z and X, and X is arylene or heteroarylene.

In certain embodiments, Y is —N(R₈)-Q-,

or —C(O)—. In certain of these embodiments, Q is selected from the groupconsisting of a bond, —C(O)—, —C(O)—O—, —S(O)₂—, —C(R₆)—N(R₈)—, and—S(O)₂—N(R₈)—; R₆ is selected from the group consisting of ═O or ═S; R₇is C₂₋₃ alkylene; R₈ is selected from the group consisting of hydrogen,C₁₋₄ alkyl, and C₁₋₄ alkoxyC₁₋₄ alkylenyl; R₁₀ is C₃₋₆ alkylene; and R₄is selected from the group consisting of alkyl, aryl, arylalkylenyl,alkylheteroarylenyl, heteroarylalkylenyl, heteroaryl, and heterocyclyl;wherein alkyl is unsubstituted or substituted by one or moresubstituents selected from the group consisting of hydroxy, alkoxy,halogen, and aryl; wherein aryl, heteroaryl, and arylalkylenyl areunsubstituted or substituted by one or more substituents selected fromthe group consisting of alkyl, halogen, cyano, dialkylamino, and alkoxy;and wherein heterocyclyl is unsubstituted or substituted by one or morealkyl substituents.

In certain embodiments, Y is —N(R₈)-Q- or

In certain of these embodiments, Q is selected from the group consistingof a bond, —C(O)—, —C(O)—O—, —S(O)₂—, and —C(R₆)—N(R₈)—; R₆ is selectedfrom the group consisting of ═O or ═S; R₇ is C₂₋₃ alkylene; R₈ isselected from the group consisting of hydrogen, C₁₋₄ alkyl, and C₁₋₄alkoxyC₁₋₄ alkylenyl; and R₄ is selected from the group consisting ofalkyl, aryl, arylalkylenyl, alkylheteroarylenyl, heteroarylalkylenyl,heteroaryl, and heterocyclyl; wherein alkyl is unsubstituted orsubstituted by one or more substituents selected from the groupconsisting of hydroxy, alkoxy, and aryl; wherein aryl and arylalkylenylare unsubstituted or substituted by one or more substituents selectedfrom the group consisting of alkyl, halogen, cyano, dialkylamino, andalkoxy; and wherein heterocyclyl is unsubstituted or substituted by oneor more alkyl substituents.

In certain embodiments, Y is —N(R₈)-Q-.

In certain embodiments, Y is selected from the group consisting of—C(O)—, —C(O)—O—, —C(O)—NH—, and —NH—C(O)—.

In certain embodiments, Y is —O—.

In certain embodiments, Y is selected from the group consisting of—C(O)—, —C(O)—O—, —S—, —NH—C(O)—, —C(O)—NH—, and —S(O)₂—NH—.

In certain embodiments, Y′ is selected from the group consisting of —O—,—S(O)₀₋₂—, —S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—, —O—C(R₆)—, —O—C(O)—O—,—N(R₉)-Q-, —C(R₆)—N(R₈)—,

In certain embodiments, Z is selected from the group consisting ofalkylene, alkenylene, and alkynylene, wherein alkylene, alkenylene, andalkynylene can be optionally interrupted with one or more —O— groups.

In certain embodiments, Z is alkylene optionally interrupted with one ormore —O— groups.

In certain embodiments, Z is selected from the group consisting of C₁₋₆alkylene and —CH₂CH₂—O—CH₂CH₂—. In certain of these embodiments, Z isselected from the group consisting of C₂₋₆ alkylene and—CH₂CH₂—O—CH₂CH₂—.

In certain embodiments, Z is a bond. For example, Z can be a bond when:R₃ is -Z-Het, -Z-Het′-R₄, or -Z-Het′-Y—R₄, and Z is attached to an atomother than N in Het or Het′; or R₃ is -Z-Y—R₄, -Z-Y—X—Y—R₄, or-Z-Y—X—Y—X—Y—R₄, and the Y group bonded to Z is —S(O)₂—, —S(O)₂—N(R₈)—,—C(R₆)—, —C(R₆)—O—, —C(R₆)—N(R₈)—,

wherein V is —C(R₆)— or —S(O)₂—, or

or

R₃ is -Z-R₅, and R₅ is

wherein V is —C(R₆)— or —S(O)₂—, or

In certain embodiments, Het is heterocyclyl which can be unsubstitutedor substituted by one or more substituents independently selected fromthe group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen,nitro, hydroxy, hydroxyalkyl, cyano, hydroxyalkyleneoxyalkylenyl, amino,alkylamino, dialkylamino, and oxo.

In certain embodiments, Het is selected from the group consisting oftetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanyl, azetidinyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,1,1-dioxothiomorpholinyl, thiazolidinyl, azepanyl, 1,4-oxazepanyl,diazepanyl, dihydroisoquinolin-(1H)-yl, octahydroisoquinolin-(1H)-yl,dihydroquinolin-(2H)-yl, octahydroquinolin-(2H)-yl,dihydro-1H-imidazolyl, 3-azabicyclo[3.2.2]non-3-yl, and piperazinyl,each of which is unsubstituted or substituted by one or moresubstituents. For these embodiments, the one or more substituents areindependently selected from the group consisting of alkyl, alkoxy,haloalkyl, haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano,hydroxyalkyleneoxyalkylenyl, amino, alkylamino, dialkylamino, and oxo.

In certain embodiments, Het is selected from the group consisting ofpyrrolidinyl, piperidinyl, and morpholinyl, each of which isunsubstituted or substituted by one or more substituents. For theseembodiments, the one or more substituents are independently selectedfrom the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, hydroxyalkyl, cyano,hydroxyalkyleneoxyalkylenyl, amino, alkylamino, dialkylamino, and oxo.

In certain embodiments, Het is substituted by one or more substituentsselected from the group consisting of alkyl, hydroxyl, hydroxyalkyl,hydroxyalkyleneoxyalkylenyl, and dialkylamino.

In certain embodiments, Het is unsubstituted.

In certain embodiments, Het′ is heterocyclylene which can beunsubstituted or substituted by one or more substituents independentlyselected from the group consisting of alkyl, alkoxy, haloalkyl,haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, amino,alkylamino, dialkylamino, and oxo.

In certain embodiments, Het′ is selected from the group consisting ofthe divalent forms of tetrahydropyranyl, tetrahydrofuranyl,1,3-dioxolanyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, 1,1-dioxothiomorpholinyl, thiazolidinyl, azepanyl,1,4-oxazepanyl, diazepanyl, dihydroisoquinolin-(1H)-yl,octahydroisoquinolin-(1H)-yl, dihydroquinolin-(2H)-yl,octahydroquinolin-(2H)-yl, dihydro-1H-imidazolyl,3-azabicyclo[3.2.2]non-3-yl, and piperazinyl, each of which isunsubstituted or substituted by one or more substituents. For theseembodiments, the one or more substituents are independently selectedfrom the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, hydroxyalkyl, cyano,hydroxyalkyleneoxyalkylenyl, amino, alkylamino, dialkylamino, and oxo.

In certain embodiments, Het′ is selected from the group consisting ofthe divalent forms of tetrahydropyranyl, tetrahydrofuranyl,1,3-dioxolanyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,thiazolidinyl, azepanyl, diazepanyl, dihydroisoquinolin-(1H)-yl,octahydroisoquinolin-(1H)-yl, dihydroquinolin-(2H)-yl,octahydroquinolin-(2H)-yl, dihydro-1H-imidazolyl, and piperazinyl, eachof which is unsubstituted or substituted by one or more substituents.For these embodiments, the one or more substituents are independentlyselected from the group consisting of alkyl, alkoxy, haloalkyl,haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano,hydroxyalkyleneoxyalkylenyl, amino, alkylamino, dialkylamino, and oxo.

In certain embodiments, Het′ is selected from the group consisting ofthe divalent forms of pyrrolidinyl, piperidinyl, and morpholinyl, eachof which is unsubstituted or substituted by one or more substituents.For these embodiments, the one or more substituents are independentlyselected from the group consisting of alkyl, alkoxy, haloalkyl,haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano,hydroxyalkyleneoxyalkylenyl, amino, alkylamino, dialkylamino, and oxo.

In certain embodiments, Het′ is unsubstituted (except by —R₄ or —Y—R₄).

In certain embodiments, a and b are independently integers from 1 to 6with the proviso that a+b is ≦7.

In certain embodiments, a and b are each independently 1, 2, or 3.

In certain embodiments, a and b are each 2.

In certain embodiments, n is 0 or 1.

In certain embodiments, n is 0.

For certain embodiments of the compounds of Formulas I, II, III, IV, V,or VI, the —NH₂ group can be replaced by an —NH-G group, as shown in thecompound of Formula VII, to form prodrugs. In such embodiments, G isselected from the group consisting of —C(O)—R′, α-aminoacyl,α-aminoacyl-α-aminoacyl, —C(O)—O—R′, —C(O)—N(R′″)R′, —C(═NY₁)—R′,—CH(OH)—C(O)—OY₁, —CH(OC₁₋₄ alkyl)Y₀, —CH₂Y₂, and —CH(CH₃)Y₂. For theseembodiments, R′ and R′″ are independently selected from the groupconsisting of C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, phenyl, and benzyl, each ofwhich may be unsubstituted or substituted by one or more substituentsindependently selected from the group consisting of halogen, hydroxy,nitro, cyano, carboxy, C₁₋₆ alkyl, C₁₋₄ alkoxy, aryl, heteroaryl,aryl-C₁₋₄ alkylenyl, heteroaryl-C₁₋₄ alkylenyl, halo-C₁₋₄ alkylenyl,halo-C₁₋₄ alkoxy, —O—C(O)—CH₃, —C(O)—O—CH₃, —C(O)—NH₂, —O—CH₂—C(O)—NH₂,—NH₂, and —S(O)₂—NH₂ with the proviso that R′″ can also be hydrogen;α-aminoacyl is an α-aminoacyl group derived from an amino acid selectedfrom the group consisting of racemic, D-, and L-amino acids; Y₁ isselected from the group consisting of hydrogen, C₁₋₆ alkyl, and benzyl;Y₀ is selected from the group consisting of C₁₋₆ alkyl, carboxy-C₁₋₆alkylenyl, amino-C₁₋₄ alkylenyl, mono-N—C₁₋₆ alkylamino-C₁₋₄ alkylenyl,and di-N,N—C₁₋₆ alkylamino-C₁₋₄ alkylenyl; and Y₂ is selected from thegroup consisting of mono-N—C₁₋₆ alkylamino, di-N,N—C₁₋₆ alkylamino,morpholin-4-yl, piperidin-1-yl, pyrrolidin-1-yl, and 4-C₁₋₄alkylpiperazin-1-yl.

For certain embodiments, the present invention provides a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundor salt of any one of the above embodiments of Formulas I, II, III, IV,V, VI, VII, X, and XI and a pharmaceutically acceptable carrier.

For certain embodiments, the present invention provides a method ofinducing cytokine biosynthesis in an animal comprising administering aneffective amount of a compound or salt of any one of the aboveembodiments of Formulas I, II, III, IV, V, VI, VII, X, and XI, or apharmaceutical composition comprising an effective amount of a compoundor salt of any one of the above embodiments of Formulas I, II, III, IV,V, VI, VII, X, and XI to the animal.

For certain embodiments, the present invention provides a method oftreating a viral disease in an animal comprising administering atherapeutically effective amount of a compound or salt of any one of theabove embodiments of Formulas I, II, III, IV, V, VI, VII, X, and XI, ora pharmaceutical composition comprising a therapeutically effectiveamount of a compound or salt of any one of the above embodiments ofFormulas I, II, III, IV, V, VI, VII, X, and XI to the animal.

For certain embodiments, the present invention provides a method oftreating a neoplastic disease in an animal comprising administering atherapeutically effective amount of a compound or salt of any one of theabove embodiments of Formulas I, II, III, IV, V, VI, VII, X, and XI, ora pharmaceutical composition comprising a therapeutically effectiveamount of a compound or salt of any one of the above embodiments ofFormulas I, II, III, IV, V, VI, VII, X, and XI to the animal.

Preparation of the Compounds

Compounds of the invention may be synthesized by synthetic routes thatinclude processes analogous to those well known in the chemical arts,particularly in light of the description contained herein. The startingmaterials are generally available from commercial sources such asAldrich Chemicals (Milwaukee, Wis., USA) or are readily prepared usingmethods well known to those skilled in the art (e.g. prepared by methodsgenerally described in Louis F. Fieser and Mary Fieser, Reagents forOrganic Synthesis, v. 1-19, Wiley, New York, (1967-1999 ed.); Alan R.Katritsky, Otto Meth-Cohn, Charles W. Rees, Comprehensive OrganicFunctional Group Transformations, v 1-6, Pergamon Press, Oxford,England, (1995); Barry M. Trost and Ian Fleming, Comprehensive OrganicSynthesis, v. 1-8, Pergamon Press, Oxford, England, (1991); orBeilsteins Handbuch der organischen Chemie, 4, Aufl. Ed.Springer-Verlag, Berlin, Germany, including supplements (also availablevia the Beilstein online database)).

For illustrative purposes, the reaction schemes depicted below providepotential routes for synthesizing the compounds of the present inventionas well as key intermediates. For more detailed description of theindividual reaction steps, see the EXAMPLES section below. Those skilledin the art will appreciate that other synthetic routes may be used tosynthesize the compounds of the invention. Although specific startingmaterials and reagents are depicted in the reaction schemes anddiscussed below, other starting materials and reagents can be easilysubstituted to provide a variety of derivatives and/or reactionconditions. In addition, many of the compounds prepared by the methodsdescribed below can be further modified in light of this disclosureusing conventional methods well known to those skilled in the art.

In the preparation of compounds of the invention it may sometimes benecessary to protect a particular functionality while reacting otherfunctional groups on an intermediate. The need for such protection willvary depending on the nature of the particular functional group and theconditions of the reaction step. Suitable amino protecting groupsinclude acetyl, trifluoroacetyl, tert-butoxycarbonyl (Boc),benzyloxycarbonyl, and 9-fluorenylmethoxycarbonyl (Fmoc). Suitablehydroxy protecting groups include acetyl and silyl groups such as thetert-butyl dimethylsilyl group. For a general description of protectinggroups and their use, see T. W. Greene and P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, New York, USA, 1991.

Conventional methods and techniques of separation and purification canbe used to isolate compounds of the invention or pharmaceuticallyacceptable salts thereof, as well as various intermediates relatedthereto. Such techniques may include, for example, all types ofchromatography (high performance liquid chromatography (HPLC), columnchromatography using common absorbents such as silica gel, and thinlayer chromatography, recrystallization, and differential (i.e.,liquid-liquid) extraction techniques.

Compounds of the invention can be prepared according to Reaction SchemeI, where R, R₂, R₃, and n are as defined above. In step (1) of ReactionScheme I, a benzyloxyaniline of Formula XV is treated with thecondensation product generated from 2,2-dimethyl-1,3-dioxane-4,6-dione(Meldrum's acid) and triethyl orthoformate to provide an imine ofFormula XVI. The reaction can be conveniently carried out by adding asolution of a benzyloxyaniline of Formula XV to a heated mixture ofMeldrum's acid and triethyl orthoformate and heating the reaction at anelevated temperature such as 45° C.

In step (2) of Reaction Scheme I, an imine of Formula XVI undergoesthermolysis and cyclization to provide a benzyloxyquinolin-4-ol ofFormula XVII. The reaction can be conveniently carried out in a mediumsuch as DOWTHERM A heat transfer fluid at a temperature in the range of200° C. to 250° C.

In step (3) of Reaction Scheme I, the benzyloxyquinolin-4-ol of FormulaXVII is nitrated under conventional nitration conditions to provide abenzyloxy-3-nitroquinolin-4-ol of Formula XVIII. The reaction can beconveniently carried out by adding nitric acid to thebenzyloxyquinolin-4-ol of Formula XVII in a suitable solvent such aspropionic acid and heating the mixture at an elevated temperature suchas 125° C.

In step (4) of Reaction Scheme I, a benzyloxy-3-nitroquinolin-4-ol ofFormula XVIII is reduced to provide a 3-amino-benzyloxyquinolin-4-ol ofFormula XIX or a salt thereof, such as the hydrochloride salt thereof.The reaction can be carried out by hydrogenation using a heterogeneoushydrogenation catalyst such as platinum on carbon. The hydrogenation isconveniently carried out in a Parr apparatus in a suitable solvent suchas N,N-dimethylformamide (DMF). The reaction can be carried out at roomtemperature.

In step (5) of Reaction Scheme I, a 3-amino benzyloxyquinolin-4-ol ofFormula XIX is reacted with a carboxylic acid or an equivalent thereofto provide a compound of Formula XX. Suitable equivalents to carboxylicacid include acid anhydrides and acid chlorides. The selection of thecarboxylic acid equivalent is determined by the desired substituent atR₂. For example, the use of butyryl chloride provides a compound inwhich R₂ is a propyl group; the use of ethoxyacetyl chloride provides acompound in which R₂ is an ethoxymethyl group. The reaction can beconveniently carried out by adding the acid chloride to a solution of a3-aminobenzyloxyquinolin-4-ol of Formula XIX in a suitable solvent suchas dichloromethane or acetonitrile in the presence of a tertiary aminesuch as triethylamine, pyridine, or 4-dimethylaminopyridine (DMAP) toafford an amide. The reaction can be carried out at or below roomtemperature. The amide of Formula XX can optionally be isolated andpurified.

In step (6) of Reaction Scheme I, an amide of Formula XX is reacted withphosphorus pentasulfide to provide abenzyloxy[1,3]thiazolo[4,5-c]quinoline of Formula XXI. The reaction canbe carried out by adding phosphorus pentasulfide to a solution orsuspension of a compound of Formula XX in a suitable solvent such aspyridine and heating the resulting mixture at an elevated temperature,for example, the reflux temperature of the solvent.

In step (7) of Reaction Scheme I, abenzyloxy[1,3]thiazolo[4,5-c]quinoline of Formula XXI is oxidized toprovide a benzyloxy[1,3]thiazolo[4,5-c]quinoline-5N-oxide of FormulaXXII using a conventional oxidizing agent capable of forming N-oxides.The reaction can be conveniently carried out by adding3-chloroperoxybenzoic acid to a solution of a compound of Formula XXI ina solvent such dichloromethane or chloroform. The reaction can becarried out at room temperature.

In step (8) of Reaction Scheme I, abenzyloxy[1,3]thiazolo[4,5-c]quinoline-5N-oxide of Formula XXII isaminated to provide a benzyloxy[1,3]thiazolo[4,5-c]quinolin-4-amine ofFormula XXIII. Step (8) can be carried out by the activation of anN-oxide of Formula XXII by conversion to an ester and then reacting theester with an aminating agent. Suitable activating agents include alkyl-or arylsulfonyl chlorides such as benzenesulfonyl chloride,methanesulfonyl chloride, or p-toluenesulfonyl chloride. Suitableaminating agents include ammonia, in the form of ammonium hydroxide, forexample, and ammonium salts such as ammonium carbonate, ammoniumbicarbonate, and ammonium phosphate. The reaction can be convenientlycarried out by adding ammonium hydroxide followed by p-toluenesulfonylchloride to a solution of the N-oxide of Formula XXII in a suitablesolvent such as 1,2-dichloroethane at elevated temperature, for example65° C. The reaction may also be carried out by adding ammonium hydroxideand p-toluenesulfonyl chloride to the reaction mixture from step (7)without isolating the N-oxide of Formula XXII.

Alternatively step (8) can be carried out by the reaction of abenzyloxy[1,3]thiazolo[4,5-c]quinoline-5N-oxide of Formula XXII withtrichloroacetyl isocyanate followed by hydrolysis of the resultingintermediate to provide a benzyloxy[1,3]thiazolo[4,5-c]quinolin-4-amineof Formula XXIII. The reaction can be conveniently carried out in twosteps by (i) adding trichloroacetyl isocyanate to a solution of theN-oxide of Formula XXII in a solvent such as dichloromethane andstirring at room temperature to provide an isolable amide intermediate.In step (ii), a solution of the intermediate in methanol is treated witha base such as sodium methoxide or ammonium hydroxide at roomtemperature.

In step (9) of Reaction Scheme I, the benzyl group of abenzyloxy[1,3]thiazolo[4,5-c]quinolin-4-amine of Formula XXIII iscleaved to provide a [1,3]thiazolo[4,5-c]quinolinol of Formula XXIV. Thecleavage is conveniently carried out with an acid such as hydrogenbromide in a suitable solvent such as acetic acid at an elevatedtemperature, such as 65° C. Alternatively, the cleavage may be carriedout on a Parr apparatus under hydrogenolysis conditions using a suitableheterogeneous catalyst such as palladium on carbon in a solvent such asethanol.

In step (10) of Reaction Scheme I, a [1,3]thiazolo[4,5-c]quinolinol ofFormula XXIV is converted to an ether-substituted[1,3]thiazolo[4,5-c]quinolin-4-amine of Formula II using aWilliamson-type ether synthesis. The reaction is effected by treating a[1,3]thiazolo[4,5-c]quinolinol of Formula XXIV with an alkyl halide ofFormula Halide-R₃ in the presence of a base. The reaction can beconveniently carried out by combining the alkyl halide with a[1,3]thiazolo[4,5-c]quinolinol of Formula XXIV in a solvent such as DMFin the presence of a suitable base such as cesium carbonate. Thereaction can be carried out at ambient temperature or at an elevatedtemperature, for example 60° C. to 85° C. Alternatively, the reactioncan be carried out by treating a solution of a[1,3]thiazolo[4,5-c]quinolinol of Formula XXIV in a solvent such as DMFwith sodium hydride and then adding a reagent of Formula Halide-R₃.

Numerous reagents of Formulas Halide-Z-Y—R₄ and Halide-Z-Het, wherein Z,Y, R₄, and Het are as defined above, are commercially available. Theseinclude, for example, bromo-substituted ketones such as2-bromoacetophenone and 2-bromo-1-(3-thienyl)-1-ethanone,bromo-substituted esters such as ethyl bromoacetate, andbromoalkyl-substituted heterocycles such as2-(bromomethyl)tetrahydro-2H-pyran. Other reagents of FormulasHalide-Z-Y—R₄, Halide-Z-R₅, Halide-Z-Y—X—Y—R₄, and Halide-Z-Het, whereinZ, Y, X, R₄, R₅, and Het are as defined above, can be prepared usingconventional synthetic methods; for example, a bromo-substituted acidhalide of Formula ClC(O)-Z-Br or BrC(O)-Z-Br can be treated with asecondary amine in a suitable solvent such as dichloromethane to providea variety of bromo-substituted amides of Formula Br-Z-C(O)—N(R₈)—R₄,

wherein R₈, R₁₀, A, a, and b are as defined above. The reaction can berun at a sub-ambient temperature such as −25° C.

Dimers of Formula II, wherein R₃ is -Z-O—R₄, wherein Z is selected fromthe group consisting of alkylene, alkenylene, and alkynylene whereinalkylene, alkenylene, and alkynylene can be optionally interrupted withone or more —O— groups, and R₄ is a [1,3]thiazolo[4,5-c]quinolineoptionally substituted as defined in R₄ above, can be prepared in step(10) of Reaction Scheme I if half an equivalent of a dialkyl halide ofFormula Halide-Z-Halide is used, and the reaction can be carried outaccording to the conditions described above.

Step (10) of Reaction Scheme I can alternatively be carried out bytreating a [1,3]thiazolo[4,5-c]quinolinol of Formula XXIV with analcohol of Formula HO—R₃ under Mitsunobu reaction conditions. Numerousalcohols of Formulas HO-Z-Y—R₄, HO-Z-R₅, and HO-Z-Het are commerciallyavailable, such as, for example, 1-(2-hydroxyethyl)pyrrolidin-2-one,1-(3-hydroxypropyl)pyrrolidin-2-one, 3-(methylthio)propan-1-ol, and3-hydroxytetrahydrofuran; other alcohols of Formula HO—R₃ can beprepared using conventional synthetic methods. The reaction can beconveniently carried out by out by adding triphenylphosphine and analcohol of Formula HO—R₃ to a solution of a[1,3]thiazolo[4,5-c]quinolinol of Formula XXIV in a suitable solventsuch as tetrahydrofuran and then slowly adding diisopropylazodicarboxylate or diethyl azodicarboxylate. The reaction can becarried out at or below room temperature, for example, at 0° C.

Compounds of the invention can be prepared according to Reaction SchemeII, where R, R₂, R₃, and n are as defined above. In step (1) of ReactionScheme II, the benzyl group of a benzyloxy[1,3]thiazolo[4,5-c]quinolineof Formula XXI is cleaved to provide a [1,3]thiazolo[4,5-c]quinolinol ofFormula XXV. The reaction can be carried out as described in step (9) ofReaction Scheme I.

In step (2) of Reaction Scheme II, a [1,3]thiazolo[4,5-c]quinolinol ofFormula XXV is converted to an ether-substituted[1,3]thiazolo[4,5-c]quinoline of Formula XII. The reaction can becarried out using one of the methods described in step (10) of ReactionScheme I.

In steps (3) and (4) of Reaction Scheme II, an ether-substituted[1,3]thiazolo[4,5-c]quinoline of Formula XII is oxidized to afford a[1,3]thiazolo[4,5-c]quinoline-5N-oxide of Formula XXVI, which isaminated to provide a [1,3]thiazolo[4,5-c]quinolin-4-amine of FormulaII. Steps (3) and (4) can be carried out as described in steps (7) and(8), respectively, of Reaction Scheme I.

Synthetic transformations can be made at R₂ in compounds of FormulasXXI, XXIII, XXIV, XXV, XII, or II, shown in Reaction Scheme I or II, if,for example, the carboxylic acid or equivalent thereof used in step (5)of Reaction Scheme I contains a protected hydroxy or amino group. Someacid chlorides of this type, for example acetoxyacetyl chloride, arecommercially available. Others can be prepared by known syntheticmethods. A protected hydroxy or amino group thus installed at R₂ canthen be deprotected by a variety of methods well-known to one of skillin the art. For example, an acetate group, installed by usingacetoxyacetyl chloride as the carboxylic acid equivalent in step (5) ofReaction Scheme I, is readily hydrolyzed under basic conditions toprovide a hydroxy group. The resulting hydroxy group can then beoxidized to an aldehyde or carboxylic acid or converted to a leavinggroup such as, for example, a chloro group using thionyl chloride or atrifluoromethanesulfonate group using trifluoromethanesulfonicanhydride. The resulting leaving group can then be displaced by avariety of nucleophiles. Sodium azide can be used as the nucleophile toinstall an azide group, which can then be reduced to an amino groupusing heterogeneous hydrogenation conditions. The amino group can thenbe converted to an amide, sulfonamide, sulfamide, or urea using one ofthe many methods described below in step (7) of Reaction Scheme IV. Aleaving group at R₂, such as a chloro or trifluoromethanesulfonategroup, can also be displaced with a secondary amine, a substitutedphenol, or a mercaptan under the conditions described below in step (2)of Reaction Scheme VI to provide a variety of compounds. For otherexamples of the installation of a variety of R₂ groups, see U.S. Pat.No. 6,110,929 (Gerster et al.).

A hydroxyalkylenyl group can also be introduced at R₂ by thedemethylation of a methoxyalkylenyl group, which can be installed byusing a methoxy-substituted carboxylic acid equivalent, for example,methoxyacetyl chloride and 2-methoxypropionyl chloride, in step (5) ofReaction Scheme I. The demethylation can be carried out by treating acompound of Formula II wherein R₂ is a methoxyalkylenyl group with borontribromide in a suitable solvent such as dichloromethane at asub-ambient temperature such as 0° C.

Synthetic elaborations can also be carried out at the R₃ group incompounds prepared in either Reaction Scheme I or II. For example, an R₃group in a compound of Formula XII may contain a —S— functional group,which can be oxidized to —S(O)₂— in step (3) of Reaction Scheme II usingan excess of the oxidizing agent. Step (4) of Reaction Scheme II maythen be carried out to provide a compound of Formula II, wherein R₃contains a —S(O)₂— functional group. In another example, an R₃ group ina compound of Formula II may be -Z-Y—R₄, wherein Y is —C(O)—. A ketoneof this formula can then be converted to an oxime by adding an aqueoussolution of a hydroxylamine salt of formula NH₂OR₈.HCl to a solution ofthe ketone in a suitable solvent such as methanol or ethanol and thenadding a base such as sodium hydroxide and heating at an elevatedtemperature to provide a compound of the invention, wherein R₃ is-Z-Y—R₄ where Y is —C(═N—OR₈)—, and R₄ and R₈ are as defined above. Theoxime so prepared may be reduced with sodium cyanoborohydride in amixture of ethanol or methanol in acetic acid to provide ahydroxylamine, which may be treated with one of numerous acid chlorides,sulfonyl chloride, isocyanates, carbamoyl chloride, or sulfamoylchlorides using one of the methods described in step (7) of ReactionScheme IV below to provide a compound of the invention wherein R₃ is-Z-Y—R₄ where Y is —CH(—N—(OR₈)-Q-R₄)—, and Q, R₄, and R₈ are as definedabove.

Compounds of the invention can be prepared according to Reaction SchemeIII where R, R₂, R₃, and n are as defined above. Reaction Scheme III isanalogous to Reaction Scheme I, with a benzyloxypyridine of FormulaXXVII used as the starting material in Reaction Scheme III instead of abenzyloxyaniline of Formula XV. Benzyloxypyridines of Formula XXVII canbe prepared using conventional synthetic methods; see for example,Holladay et al., Biorg. Med. Chem. Lett., 8, pp. 2797-2802, (1998).Isomers of the compounds of Formula XXVII and Formula XXIX, wherein N isat a different position in the pyridine ring, can also be synthesizedand can be used in Reaction Scheme III to prepare compounds of theinvention. Steps (1) through (10) of Reaction Scheme III can be runusing the same conditions described in steps (1) through (10) ofReaction Scheme I.

For some embodiments, compounds of the invention can be preparedaccording to Reaction Scheme IV, where R, R₂, R₈, and n are defined asabove; Z is selected from the group consisting of alkylene, alkenylene,and alkynylene wherein alkylene, alkenylene, and alkynylene can beoptionally interrupted with one or more —O— groups; and R_(3a) is-Z-N(R₈)-Q-R₄ or

with R₈, R₁₀, Q, and R₄ as defined above; -Z-R₅, wherein R₅ is

with A, a, b, R₇, and R₈ as defined above; or -Z-[N(R₈)-Q]-X—O—R₄ or-Z-[N(R₈)-Q]-X—[V—N(R₈)]-X—O—R₄, wherein X and V are as defined above,and R₄ is a [1,3]thiazolo[4,5-c]quinoline optionally substituted asdefined in R₄ above.

In step (1) of Reaction Scheme IV, the amine of an amino alcohol ofFormula XXXVII is protected with a tert-butoxy carbonyl (Boc) group toprovide a hydroxyalkylcarbamate of Formula XXXVIII. Numerous aminoalcohols of Formula XXXVII are commercially available; others can beprepared using known synthetic methods. The reaction can be convenientlycarried out by treating the amino alcohol of Formula XXXVII withdi-tert-butyl dicarbonate optionally in the presence of a base such asaqueous sodium hydroxide. The reaction can be run at room temperature ina suitable solvent such as tetrahydrofuran or dichloromethane.

In step (2) of Reaction Scheme IV, a hydroxyalkylcarbamate of FormulaXXXVIII is converted to an iodoalkylcarbamate of Formula XXXIX usingconventional methods. The reaction can be conveniently carried out bytreating the hydroxyalkylcarbamate of Formula XXXVIII with a solution ofiodine, triphenylphosphine, and imidazole. The reaction can be run atroom temperature in a suitable solvent such as dichloromethane orsolvent mixture such as diethyl ether/acetonitrile.

In step (3) of Reaction Scheme IV, a [1,3]thiazolo[4,5-c]quinolinol ofFormula XXV is treated with an iodoalkylcarbamate of Formula XXXIX toprovide an ether-substituted [1,3]thiazolo[4,5-c]quinoline of FormulaXL. The reaction can be carried out according to the Williamsonconditions described in step (10) of Reaction Scheme I.

In steps (4) and (5) of Reaction Scheme IV, a[1,3]thiazolo[4,5-c]quinoline of Formula XL is oxidized to a[1,3]thiazolo[4,5-c]quinoline-5N-oxide of Formula XLI, which is aminatedto provide a [1,3]thiazolo[4,5-c]quinolin-4-amine of Formula XLII, whichis a subgenus Formulas I and II. Steps (4) and (5) of Reaction Scheme IVcan be carried out as described for steps (7) and (8), respectively, ofReaction Scheme I. In step (5), the preferred conditions for aminationare the activation of an N-oxide of Formula XLI by conversion to anester and then reacting the ester with an aminating agent. Step (5) isconveniently carried out by adding ammonium hydroxide to a solution ofthe N-oxide of Formula XLI in a suitable solvent such as1,2-dichloroethane and then adding p-toluenesulfonyl chloride andstirring at an elevated temperature such as 65° C.

In step (6) of Reaction Scheme IV, the Boc protecting group of a[1,3]thiazolo[4,5-c]quinolin-4-amine of Formula XLII is removed toprovide an amino-substituted [1,3]thiazolo[4,5-c]quinolin-4-amine ofFormula XLIII, which is a subgenus of Formulas I and II. The reactioncan be conveniently carried out by adding a solution of hydrochloricacid in ethanol to a [1,3]thiazolo[4,5-c]quinolin-4-amine of FormulaXLII. The reaction can be carried out at an elevated temperature, forexample, the reflux temperature of the solvent.

In step (7) of Reaction Scheme IV, an amino-substituted[1,3]thiazolo[4,5-c]quinolin-4-amine of Formula XLIII is converted to a[1,3]thiazolo[4,5-c]quinolinyl compound of Formula IIa, a subgenus ofFormulas I and II, using conventional methods. For example, anamino-substituted [1,3]thiazolo[4,5-c]quinolin-4-amine of Formula XLIIIcan react with an acid chloride of Formula R₄C(O)Cl to provide acompound of Formula IIa in which R_(3a) is -Z-N(R₈)—C(O)—R₄. Inaddition, a [1,3]thiazolo[4,5-c]quinolin-4-amine of Formula XLIII canreact with sulfonyl chloride of Formula R₄S(O)₂Cl or a sulfonicanhydride of Formula (R₄S(O)₂)₂O to provide a compound of Formula IIa inwhich R_(3a) is -Z-N(R₈)—S(O)₂—R₄. Numerous acid chlorides of FormulaR₄C(O)Cl, sulfonyl chlorides of Formula R₄S(O)₂Cl, and sulfonicanhydrides of Formula (R₄S(O)₂)₂O are commercially available; others canbe readily prepared using known synthetic methods. The reaction can beconveniently carried out by adding the acid chloride of FormulaR₄C(O)Cl, sulfonyl chloride of Formula R₄S(O)₂Cl, or sulfonic anhydrideof Formula (R₄S(O)₂)₂O to a solution of the amino-substituted[1,3]thiazolo[4,5-c]quinolin-4-amine of Formula XLIII in a suitablesolvent such as chloroform, dichloromethane, N,N-dimethylacetamide(DMA), or 1-methyl-2-pyrrolidinone. Optionally a base such astriethylamine, pyridine, or N,N-diisopropylethylamine, or catalyticDMAP, or a combination thereof can be added. The reaction can be carriedout at room temperature or initially at a sub-ambient temperature suchas 0° C. and then warming to room temperature.

Compounds of Formula IIa where R_(3a) is -Z-R₅ and R₅ is

can be prepared by treating an amino-substituted[1,3]thiazolo[4,5-c]quinolin-4-amine of Formula XLIII, wherein R₈ ishydrogen, with a chloroalkanesulfonyl chloride of Formula Cl—R₇S(O)₂Clor a chloroalkanoyl chloride of Formula C₁—R₇C(O)Cl. The reaction can beconveniently carried out by adding the chloroalkanesulfonyl chloride orchloroalkanoyl chloride to a solution of the amino-substituted[1,3]thiazolo[4,5-c]quinolin-4-amine of Formula XLIII in a suitablesolvent such as chloroform at ambient temperature. The isolableintermediate chloroalkanesulfonamide or chloroalkanamide can then betreated with a base such as 1,8-diazabicyclo[5.4.0]undec-7-ene or sodiumhydride in a suitable solvent such as DMF to effect the cyclization.

Ureas of Formula IIa, where R_(3a) is -Z-N(R₈)-Q-R₄, Q is —C(R₆)—NH—W—,R₆ is ═O, and W is a bond, can be prepared by reacting anamino-substituted [1,3]thiazolo[4,5-c]quinolin-4-amine of Formula XLIIIwith isocyanates of Formula R₄N═C═O, Numerous isocyanates of FormulaR₄N═C═O are commercially available; others can be readily prepared usingknown synthetic methods. The reaction can be conveniently carried out byadding the isocyanate of Formula R₄N═C═O to a solution of theamino-substituted [1,3]thiazolo[4,5-c]quinolin-4-amine of Formula XLIIIin a suitable solvent such as dichloromethane, chloroform, or DMA.Optionally a base such as triethylamine can be added. The reaction canbe carried out at room temperature or initially at a sub-ambienttemperature such as 0° C. and warming to room temperature.Alternatively, a compound of Formula XLIII can be treated with anisocyanate of Formula R₄(CO)N═C═O, a thioisocyanate of Formula R₄N═C═S,a sulfonyl isocyanate of Formula R₄S(O)₂N═C═O, or a carbamoyl chlorideof Formula R₄N—(R₈)—C(O)Cl,

to provide a compound of Formula IIa, where R_(3a) is -Z-N(R₈)-Q-R₄,

wherein Q is —C(R₆)—N(R₈)—W—, where R₆, R₈, and W are defined as above.

Sulfamides of Formula IIa, where R_(3a) is -Z-N(R₈)—S(O)₂—N(R₈)—R₄ canbe prepared by reacting a compound of Formula XLIII with sulfurylchloride to generate a sulfamoyl chloride in situ, and then reacting thesulfamoyl chloride with an amine of Formula HN(R₈)R₄. Alternatively,sulfamides of Formula IIa can be prepared by reacting a compound ofFormula XLIII with a sulfamoyl chloride of Formula R₄(R₈)N—S(O)₂Cl. Manyamines of Formula HN(R₈)R₄ and some sulfamoyl chlorides of FormulaR₄(R₈)N—S(O)₂Cl are commercially available; others can be prepared usingknown synthetic methods.

Compounds of Formula IIa, wherein R_(3a) is -Z-N(R₈)—R₄ can be preparedby reductive alkylation of the amino-substituted[1,3]thiazolo[4,5-c]quinolin-4-amine of Formula XLIII, wherein R₈ ishydrogen. The alkylation is conveniently carried out in two parts by (i)adding an aldehyde or ketone to a solution of an amino-substituted[1,3]thiazolo[4,5-c]quinolin-4-amine of Formula XLIII or a salt thereofin a suitable solvent such as DMF in the presence of a base such asN,N-diisopropylethylamine. In part (ii) the reduction is carried out byadding a suitable reducing agent such as the borane-pyridine complex.Both part (i) and part (ii) can be carried out at room temperature. Incompounds of Formula XLIII, wherein R₈ is hydrogen, it is convenient tocarry out the reductive alkylation followed by reaction with an acidchloride, sulfonyl chloride, sulfonic anhydride, isocyanate, orcarbamoyl chloride as described above to provide a compound of FormulaIIa, wherein R_(3a) is -Z-N(R₈)-Q-R₄, wherein Z, R₄, R₈, and Q are asdefined above.

Dimers of Formula IIa, wherein R_(3a) is-Z-[N(R₈)-Q]-X—[V—N(R₈)]-X—O—R₄, wherein X and R₈ are as defined above,Q is selected from the group consisting of —C(R₆)—, —S(O)₂—,—C(R₆)—N(R₈)—, V is selected from the group consisting of-C(R₆)—,—N(R₈)—C(R₆)—, and —S(O)₂—, and R₄ is a [1,3]thiazolo[4,5-c]quinolineoptionally substituted as defined in R₄ above, can be prepared bytreating an amino-substituted [1,3]thiazolo[4,5-c]quinolin-4-amine ofFormula XLIII or a salt thereof with a diacid chloride, a disulfonylchloride, or a diisocyanate according to the reaction conditionsdescribed above for the reactions with acid chlorides, sulfonylchlorides, and isocyanates. Numerous diacid chlorides, disulfonylchlorides, and diisocyanates are commercially available. These includebut are not limited to aliphatic compounds such as fumaryl chloride,succinyl chloride, glutaryl chloride, sebacoyl chloride,2,2′-oxydiacetyl chloride, 1,4-butanedisulfonyl chloride,1,4-diisocyanatobutane, hexamethylene diisocyanate, and1,12-diisocyanatododecane; aromatic compounds such as1,2-benzenedisulfonyl chloride, 1,3-benzenedisulfonyl chloride,1,4-phenylene diisocyanate, 1,5-naphthalenediisocyanate, phthaloylchloride, and isophthaloyl chloride; cycloaliphatic compounds such asdicylcohexylmethane-4,4′-diisocyanate, trans-1,4-cyclohexanediisocyanate, and 1,3-bis(isocyanatomethyl)cyclohexane; heteroarylcompounds such as 2,6-pyrdinedicarbonyl chloride; and compounds such as4,4′-benzoyl chloride, 4,4′-methylene-bis(benzenesulfonyl) chloride,m-xylene diisocyanate, 4,4′-diphenylmethane diisocyanate.

Dimers of Formula IIa, wherein R_(3a) is -Z-[N(R₈)—C(O)—N(R₈)]-X—O—R₄,wherein X is as defined above, and R₄ is a [1,3]thiazolo[4,5-c]quinolineoptionally substituted as defined in R₄ above, can be prepared bytreating an amino-substituted [1,3]thiazolo[4,5-c]quinolin-4-amine ofFormula XLIII or a salt thereof with carbonyldiimidazole in a suitablesolvent such as DMF at an elevated temperature such as 75° C.

Compounds of the invention can be prepared according to Reaction SchemeV, where R, R₂, R₁₀, and n are as defined above; Z_(a) is selected fromthe group consisting of a bond, alkylene, alkenylene, and alkynylenewherein alkylene, alkenylene, and alkynylene can be optionallyinterrupted with one or more —O— groups; R_(3b) is

wherein R₄, R₆, R₁₀, A, Q, a, and b are as defined above. Steps (1)through (7) of Reaction Scheme V can be run as described in steps (1)through (7) of Reaction Scheme IV to provide compounds of Formula IIb, asubgenus of Formulas I and II.

Alternatively, a compound of Formula XLV can react with a[1,3]thiazolo[4,5-c]quinolinol of Formula XXV under the Mitsunobureaction conditions described in step (10) of Reaction Scheme I. Forexample, combining a [1,3]thiazolo[4,5-c]quinolinol of Formula XXV,triphenylphosphine, and tert-butyl 4-hydroxy-1-piperidinecarboxylate inTHF at 5° C. or room temperature and slowly adding diisopropylazodicarboxylate provides a compound of Formula XLVII wherein Z_(a) is abond and R₁₀ is pentylene.

The oxidation in step (4) of Reaction Scheme V can be carried outaccording to the reaction conditions described in step (7) of ReactionScheme I or by heating a solution of a compound of Formula XLVII in asuitable solvent such as ethyl acetate with peracetic acid at atemperature such as 50° C. and then adding sodium metabisulfate.

Compounds of the invention can also be prepared according to ReactionScheme VI, wherein R, R₂, and n are as defined above; Z is selected fromthe group consisting of alkylene, alkenylene, and alkynylene whereinalkylene, alkenylene, and alkynylene can be optionally interrupted withone or more —O— groups; and R_(3c) is -Z-Het, -Z-Het′-R₄, or-Z-Het′-Y—R₄, wherein Het or Het′ is attached to Z at a nitrogen atom.

In step (1) of Reaction Scheme VI, a [1,3]thiazolo[4,5-c]quinolinol ofFormula XXIV is treated with a dihalide of Formula I-Z-Cl or Br-Z-Clusing the Williamson conditions described in step (10) of ReactionScheme I to provide a chloro-substituted compound of Formula X.

In step (2) of Reaction Scheme VI, a chloro-substituted compound ofFormula X is treated with a cyclic secondary amine to provide a compoundof Formula IIc, a subgenus of Formulas I and II. Many cyclic secondaryamines are commercially available, such as unsubstituted or substitutedpyrrolidines, piperidines, morpholines, and piperazines; others can beprepared using conventional methods. The reaction can be convenientlycarried out by adding a cyclic secondary amine to a compound of FormulaX in a suitable solvent such as DMF. The reaction can be convenientlycarried out in the presence of a base such as potassium carbonate at anelevated temperature such as 65° C.

Compounds of Formula IIc are also prepared from[1,3]thiazolo[4,5-c]quinolinols of Formula XXV, shown in Reaction SchemeII. A [1,3]thiazolo[4,5-c]quinolinol of Formula XXV is first treatedwith a dihalide of Formula I-Z-Cl or Br-Z-Cl according to step (1) ofReaction Scheme V. The product is then oxidized and aminated accordingto the methods described in steps (7) and (8) of Reaction Scheme I toprovide a compound of Formula X, which is then treated with a cyclicsecondary amine as described in step (2) of Reaction Scheme VI toprovide a compound of Formula IIc.

A compound of Formula X is also a useful starting material to provide anumber of other compounds of the invention. For example, a compound ofFormula X can be treated with a non-cyclic secondary amine or amercaptan under the conditions described in step (2) above to provide acompound in which R_(3c) is -Z-Y—R₄, wherein R₄ is as defined above andY is —N(R₈)-Q- or —S—, wherein Q is a bond and R₈ is as defined above.In another example, a compound of Formula X can be treated under thesame conditions with a substituted phenol to provide a compound whereinR_(3c) is -Z-Y—X—Y—R₄, in which the Y bonded to Z is —O—, X isphenylene, and R₄ and the Y bonded to R₄ are as defined above or acompound wherein R_(3c) is -Z-Y—R₄, in which Y is —O—, and R₄ is phenylthat is optionally substituted. In yet another example, a compound ofFormula X can be treated with N-hydroxyphthalimide in the presence of abase, such as triethylamine, in a suitable solvent such as DMF atambient temperature. The phthalimide group can then be removed from theresulting N-phthalimide-protected hydroxylamine by treatment withhydrazine at ambient temperature in a suitable solvent such as ethanol.The resulting hydroxylamine can then be treated with one of numerouscommercially available aldehydes or ketones in a suitable solvent suchas methanol to provide a compound of Formula IIc wherein R_(3c) is-Z-Y—R₄ or -Z-R₅, where Y is —O—N═C(R₄)—, R₅ is

and R₄, a, b, and A′ are as defined above. Alternatively, thehydroxylamine prepared after the hydrazine deprotection may be treatedwith one of numerous acid chlorides, sulfonyl chloride, isocyanates,carbamoyl chloride, or sulfamoyl chlorides using one of the methodsdescribed in step (7) of Reaction Scheme IV to provide a compoundFormula IIc wherein R_(3c) is -Z-Y—R₄ where Y is —O—NH-Q-, and Q and R₄are as defined above.

Compounds of the invention can also be prepared using variations of thesynthetic routes shown in Reaction Schemes I through VI that would beapparent to one of skill in the art. For example, the synthetic routeshown in Reaction Scheme IV for the preparation of quinolines having aR_(3a) substituent can be used to prepare [1,5]naphthyridines having aR_(3a) substituent by using a [1,3]thiazolo[4,5-c][1,5]naphthyridinol inlieu of the [1,3]thiazolo[4,5-c]quinolinol. Similarly, the syntheticroutes shown in Reaction Schemes V and VII can be carried out using a[1,3]thiazolo[4,5-c][1,5]naphthyridinol instead of a[1,3]thiazolo[4,5-c]quinolinol as a starting material. Compounds of theinvention can also be prepared using the synthetic routes described inthe EXAMPLES below.

Prodrugs can be prepared in a variety of ways. For example, a compoundwherein R₃ or R₂ is —X—OH (e.g. hydroxyalkyl) can be converted into aprodrug wherein R₃ or R₂ is, for example, —X—O—C(R₆)—R₄,—X—O—C(R₆)—O—R₄, or —X—O—C(R₆)—N(R₈)—R₄, wherein X, R₄, R₆, and R₈ areas defined above, using methods known to one skilled in the art. Inaddition, a compound wherein R is hydroxy may also be converted to anester, an ether, a carbonate, or a carbamate. For any of these compoundscontaining an alcohol functional group, a prodrug can be formed by thereplacement of the hydrogen atom of the alcohol group with a group suchas C₁₋₆ alkanoyloxymethyl, 1-(C₁₋₆ alkanoyloxy)ethyl, 1-methyl-1-(C₁₋₆alkanoyloxy)ethyl, C₁₋₆ alkoxycarbonyloxymethyl, N—(C₁₋₆alkoxycarbonyl)aminomethyl, succinoyl, C₁₋₆ alkanoyl, α-aminoC₁₋₄alkanoyl, arylacyl, —P(O)(OH)₂, —P(O)(O—C₁₋₆ alkyl)₂, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylcarbamoyl, and α-aminoacyl orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from racemic, D-, and L-amino acids. For compounds containingan alcohol functional group, particularly useful prodrugs are estersmade from carboxylic acids containing one to six carbon atoms,unsubstituted or substituted benzoic acid esters, or esters made fromamino acids. The reaction conditions described above in step (7) ofReaction Scheme IV can be used.

Prodrugs can also be made from a compound containing an amino group byconversion of the amino group to a functional group such as an amide,carbamate, urea, amidine, or another hydrolyzable group usingconventional methods. A prodrug of this type can be made by thereplacement of a hydrogen atom in an amino group, particularly the aminogroup at the 4-position, with a group such as —C(O)—R′, α-aminoacyl,α-aminoacyl-α-aminoacyl, —C(O)—O—R′, —C(O)—N(R′″)—R′, —C(═NY₁)—R′,—CH(OH)—C(O)—OY₁, —CH(OC₁₋₄ alkyl)Y₀, —CH₂Y₂, or —CH(CH₃)Y₂; wherein R′and R′″ are each independently C₁₋₁₀ alkyl, C₃₋₇ cycloalkyl, phenyl, orbenzyl, each of which may be unsubstituted or substituted by one or moresubstituents independently selected from the group consisting ofhalogen, hydroxy, nitro, cyano, carboxy, C₁₋₆ alkyl, C₁₋₄ alkoxy, aryl,heteroaryl, arylC₁₋₄ alkylenyl, heteroarylC₁₋₄ alkylenyl, haloC₁₋₄alkyl, haloC₁₋₄ alkoxy, —O—C(O)—CH₃, —C(O)—O—CH₃, —C(O)—NH₂,—O—CH₂—C(O)—NH₂, —NH₂, and —S(O)₂—NH₂, with the proviso that R′″ canalso be hydrogen; each α-aminoacyl group is independently selected fromracemic, D-, and L-amino acids; Y₁ is hydrogen, C₁₋₆ alkyl, or benzyl;Y₀ is C₁₋₆ alkyl, carboxyC₁₋₆ alkylenyl, aminoC₁₋₄ alkylenyl,mono-N—C₁₋₆ alkylaminoC₁₋₄ alkylenyl, or di-N,N—C₁₋₆ alkylaminoC₁₋₄alkylenyl; and Y₂ is mono-N—C₁₋₆ alkylamino, di-N,N—C₁₋₆ alkylamino,morpholin-4-yl, piperidin-1-yl, pyrrolidin-1-yl, or 4-C₁₋₄alkylpiperazin-1-yl. For compounds containing an amine functional group,particularly useful prodrugs are amides derived from carboxylic acidscontaining one to ten carbon atoms, amides derived from racemic, D-, orL-amino acids, and carbamates containing one to ten carbon atoms. Thereaction can be carried out, for example, by combining a compound ofFormula I, II, III, IV, V, or VI with a chloroformate or acid chloride,such as ethyl chloroformate or acetyl chloride, in the presence of abase such as triethylamine in a suitable solvent such as dichloromethaneat room temperature.

Pharmaceutical Compositions and Biological Activity

Pharmaceutical compositions of the invention contain a therapeuticallyeffective amount of a compound or salt described above in combinationwith a pharmaceutically acceptable carrier.

The terms “a therapeutically effective amount” and “effective amount”mean an amount of the compound or salt sufficient to induce atherapeutic or prophylactic effect, such as cytokine induction,immunomodulation, antitumor activity, and/or antiviral activity. Theexact amount of compound or salt used in a pharmaceutical composition ofthe invention will vary according to factors known to those of skill inthe art, such as the physical and chemical nature of the compound orsalt, the nature of the carrier, and the intended dosing regimen.

In some embodiments, the compositions of the invention will containsufficient active ingredient or prodrug to provide a dose of about 100nanograms per kilogram (ng/kg) to about 50 milligrams per kilogram(mg/kg), preferably about 10 micrograms per kilogram (μg/kg) to about 5mg/kg, of the compound or salt to the subject.

In other embodiments, the compositions of the invention will containsufficient active ingredient or prodrug to provide a dose of, forexample, from about 0.01 mg/m² to about 5.0 mg/m², computed according tothe Dubois method, in which the body surface area of a subject (m²) iscomputed using the subject's body weight: m²=(wt kg^(0.425)×heightcm^(0.725))×0.007184, although in some embodiments the methods may beperformed by administering a compound or salt or composition in a doseoutside this range. In some of these embodiments, the method includesadministering sufficient compound to provide a dose of from about 0.1mg/m² to about 2.0 mg/m² to the subject, for example, a dose of fromabout 0.4 mg/m² to about 1.2 mg/m².

A variety of dosage forms may be used, such as tablets, lozenges,capsules, parenteral formulations, syrups, creams, ointments, aerosolformulations, transdermal patches, transmucosal patches and the like.These dosage forms can be prepared with conventional pharmaceuticallyacceptable carriers and additives using conventional methods, whichgenerally include the step of bringing the active ingredient intoassociation with the carrier.

The compounds or salts of the invention can be administered as thesingle therapeutic agent in the treatment regimen, or the compounds orsalts described herein may be administered in combination with oneanother or with other active agents, including additional immuneresponse modifiers, antivirals, antibiotics, antibodies, proteins,peptides, oligonucleotides, etc.

Compounds or salts of the invention have been shown to induce theproduction of certain cytokines in experiments performed according tothe tests set forth below. These results indicate that the compounds orsalts are useful for modulating the immune response in a number ofdifferent ways, rendering them useful in the treatment of a variety ofdisorders.

Cytokines whose production may be induced by the administration ofcompounds or salts of the invention generally include interferon-α(IFN-α) and tumor necrosis factor-α (TNF-α) as well as certaininterleukins (IL). Cytokines whose biosynthesis may be induced bycompounds or salts of the invention include IFN-α, TNF-α, IL-1, IL-6,IL-10 and IL-12, and a variety of other cytokines. Among other effects,these and other cytokines can inhibit virus production and tumor cellgrowth, making the compounds or salts useful in the treatment of viraldiseases and neoplastic diseases. Accordingly, the invention provides amethod of inducing cytokine biosynthesis in an animal comprisingadministering an effective amount of a compound or salt of the inventionto the animal. The animal to which the compound or salt is administeredfor induction of cytokine biosynthesis may have a disease as describedinfra, for example a viral disease or a neoplastic disease, andadministration of the compound or salt may provide therapeutictreatment. Alternatively, the compound or salt may be administered tothe animal prior to the animal acquiring the disease so thatadministration of the compound or salt may provide a prophylactictreatment.

In addition to the ability to induce the production of cytokines,compounds or salts described herein can affect other aspects of theinnate immune response. For example, natural killer cell activity may bestimulated, an effect that may be due to cytokine induction. Thecompounds or salts may also activate macrophages, which in turnstimulate secretion of nitric oxide and the production of additionalcytokines. Further, the compounds or salts may cause proliferation anddifferentiation of B-lymphocytes.

Compounds or salts described herein can also have an effect on theacquired immune response. For example, the production of the T helpertype 1 (T_(H)1) cytokine IFN-γ may be induced indirectly and theproduction of the T helper type 2 (T_(H)2) cytokines IL-4, IL-5 andIL-13 may be inhibited upon administration of the compounds or salts.

Whether for prophylaxis or therapeutic treatment of a disease, andwhether for effecting innate or acquired immunity, the compound or saltor composition may be administered alone or in combination with one ormore active components as in, for example, a vaccine adjuvant. Whenadministered with other components, the compound or salt or compositionand other component or components may be administered separately;together but independently such as in a solution; or together andassociated with one another such as (a) covalently linked or (b)non-covalently associated, e.g., in a colloidal suspension.

Conditions for which compounds or salts or compositions identifiedherein may be used as treatments include, but are not limited to:

(a) viral diseases such as, for example, diseases resulting frominfection by an adenovirus, a herpesvirus (e.g., HSV-I, HSV-II, CMV, orVZV), a poxvirus (e.g., an orthopoxvirus such as variola or vaccinia, ormolluscum contagiosum), a picornavirus (e.g., rhinovirus orenterovirus), an orthomyxovirus (e.g., influenzavirus), a paramyxovirus(e.g., parainfluenzavirus, mumps virus, measles virus, and respiratorysyncytial virus (RSV)), a coronavirus (e.g., SARS), a papovavirus (e.g.,papillomaviruses, such as those that cause genital warts, common warts,or plantar warts), a hepadnavirus (e.g., hepatitis B virus), aflavivirus (e.g., hepatitis C virus or Dengue virus), or a retrovirus(e.g., a lentivirus such as HIV);

(b) bacterial diseases such as, for example, diseases resulting frominfection by bacteria of, for example, the genus Escherichia,Enterobacter, Salmonella, Staphylococcus, Shigella, Listeria,Aerobacter, Helicobacter, Klebsiella, Proteus, Pseudomonas,Streptococcus, Chlamydia, Mycoplasma, Pneumococcus, Neisseria,Clostridium, Bacillus, Corynebacterium, Mycobacterium, Campylobacter,Vibrio, Serratia, Providencia, Chromobacterium, Brucella, Yersinia,Haemophilus, or Bordetella;

(c) other infectious diseases, such as chlamydia, fungal diseasesincluding but not limited to candidiasis, aspergillosis, histoplasmosis,cryptococcal meningitis, or parasitic diseases including but not limitedto malaria, pneumocystis carnii pneumonia, leishmaniasis,cryptosporidiosis, toxoplasmosis, and trypanosome infection;

(d) neoplastic diseases, such as intraepithelial neoplasias, cervicaldysplasia, actinic keratosis, basal cell carcinoma, squamous cellcarcinoma, renal cell carcinoma, Kaposi's sarcoma, melanoma, leukemiasincluding but not limited to acute myeloid leukemia, acute lymphocyticleukemia, chronic myeloid leukemia, chronic lymphocytic leukemia,multiple myeloma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, cutaneousT-cell lymphoma, B-cell lymphoma, and hairy cell leukemia, and othercancers;

(e) T_(H)2-mediated, atopic diseases, such as atopic dermatitis oreczema, eosinophilia, asthma, allergy, allergic rhinitis, and Ommen'ssyndrome;

(f) certain autoimmune diseases such as systemic lupus erythematosus,essential thrombocythaemia, multiple sclerosis, discoid lupus, alopeciagreata; and

(g) diseases associated with wound repair such as, for example,inhibition of keloid formation and other types of scarring (e.g.,enhancing wound healing, including chronic wounds).

Additionally, a compound or salt identified herein may be useful as avaccine adjuvant for use in conjunction with any material that raiseseither humoral and/or cell mediated immune response, such as, forexample, live viral, bacterial, or parasitic immunogens; inactivatedviral, tumor-derived, protozoal, organism-derived, fungal, or bacterialimmunogens; toxoids; toxins; self-antigens; polysaccharides; proteins;glycoproteins; peptides; cellular vaccines; DNA vaccines; autologousvaccines; recombinant proteins; and the like, for use in connectionwith, for example, BCG, cholera, plague, typhoid, hepatitis A, hepatitisB, hepatitis C, influenza A, influenza B, parainfluenza, polio, rabies,measles, mumps, rubella, yellow fever, tetanus, diphtheria, hemophilusinfluenza b, tuberculosis, meningococcal and pneumococcal vaccines,adenovirus, HIV, chicken pox, cytomegalovirus, dengue, feline leukemia,fowl plague, HSV-1 and HSV-2, hog cholera, Japanese encephalitis,respiratory syncytial virus, rotavirus, papilloma virus, yellow fever,and Alzheimer's Disease.

Compounds or salts identified herein may be particularly helpful inindividuals having compromised immune function. For example, compoundsor salts may be used for treating the opportunistic infections andtumors that occur after suppression of cell mediated immunity in, forexample, transplant patients, cancer patients and HIV patients.

Thus, one or more of the above diseases or types of diseases, forexample, a viral disease or a neoplastic disease may be treated in ananimal in need thereof (having the disease) by administering atherapeutically effective amount of a compound or salt of the inventionto the animal.

An animal may also be vaccinated by administering an effective amount ofa compound or salt described herein, as a vaccine adjuvant. In oneembodiment, there is provided a method of vaccinating an animalcomprising administering an effective amount of a compound or saltdescribed herein to the animal as a vaccine adjuvant.

An amount of a compound or salt effective to induce cytokinebiosynthesis is an amount sufficient to cause one or more cell types,such as monocytes, macrophages, dendritic cells and B-cells to producean amount of one or more cytokines such as, for example, IFN-α, TNF-α,IL-1, IL-6, IL-10 and IL-12 that is increased (induced) over abackground level of such cytokines. The precise amount will varyaccording to factors known in the art but is expected to be a dose ofabout 100 ng/kg to about 50 mg/kg, preferably about 10 μg/kg to about 5mg/kg. In other embodiments, the amount is expected to be a dose of, forexample, from about 0.01 mg/m² to about 5.0 mg/m², (computed accordingto the Dubois method as described above) although in some embodimentsthe induction or inhibition of cytokine biosynthesis may be performed byadministering a compound or salt in a dose outside this range. In someof these embodiments, the method includes administering sufficientcompound or salt or composition to provide a dose of from about 0.1mg/m² to about 2.0 mg/m² to the subject, for example, a dose of fromabout 0.4 mg/m² to about 1.2 mg/m².

The invention also provides a method of treating a viral infection in ananimal and a method of treating a neoplastic disease in an animalcomprising administering an effective amount of a compound or salt ofthe invention to the animal. An amount effective to treat or inhibit aviral infection is an amount that will cause a reduction in one or moreof the manifestations of viral infection, such as viral lesions, viralload, rate of virus production, and mortality as compared to untreatedcontrol animals. The precise amount that is effective for such treatmentwill vary according to factors known in the art but is expected to be adose of about 100 ng/kg to about 50 mg/kg, preferably about 10 μg/kg toabout 5 mg/kg. An amount of a compound or salt effective to treat aneoplastic condition is an amount that will cause a reduction in tumorsize or in the number of tumor foci. Again, the precise amount will varyaccording to factors known in the art but is expected to be a dose ofabout 100 ng/kg to about 50 mg/kg, preferably about 10 μg/kg to about 5mg/kg. In other embodiments, the amount is expected to be a dose of, forexample, from about 0.01 mg/m² to about 5.0 mg/m², (computed accordingto the Dubois method as described above) although in some embodimentseither of these methods may be performed by administering a compound orsalt in a dose outside this range. In some of these embodiments, themethod includes administering sufficient compound or salt to provide adose of from about 0.1 mg/m² to about 2.0 mg/m² to the subject, forexample, a dose of from about 0.4 mg/m² to about 1.2 mg/m².

In addition to the formulations and uses described specifically herein,other formulations, uses, and administration devices suitable forcompounds of the present invention are described in, for example,International Publication Nos. WO 03/077944 and WO 02/036592, U.S. Pat.No. 6,245,776, and U.S. Publication Nos. 2003/0139364, 2003/185835,2004/0258698, 2004/0265351, 2004/076633, and 2005/0009858.

Objects and advantages of this invention are further illustrated by thefollowing examples, but the particular materials and amounts thereofrecited in these examples, as well as other conditions and details,should not be construed to unduly limit this invention.

EXAMPLES Example 17-(2-Morpholin-4-ylethoxy)-2-propyl[1,3]thiazolo[4,5-c]quinolin-4-amine

Part A

A mixture of triethyl orthoformate (92 milliliters (mL), 0.55 moles(mol)) and 2,2-dimethyl-[1,3]-dioxane-4,6-dione (75.3 grams (g), 0.522mol) (Meldrum's acid) was heated at 55° C. for 90 minutes and thencooled to 45° C. A solution of 3-benzyloxyaniline (100.2 g, 0.5029 mol)in methanol (200 mL) was slowly added to the reaction over a period 45minutes while maintaining the reaction temperature below 50° C. Thereaction was then heated at 45° C. for one hour, allowed to cool to roomtemperature, and stirred overnight. The reaction mixture was cooled to1° C., and the product was isolated by filtration and washed with coldethanol (approximately 400 mL) until the filtrate was colorless.5-{[(3-Benzyloxy)phenylimino]methyl}-2,2-dimethyl-[1,3]-dioxane-4,6-dione(170.65 g) was isolated as a tan, powdery solid. ¹H NMR (300 MHz,DMSO-d₆) δ 11.21 (d, J=14.2 Hz, 1H), 8.61 (d, J=14.2 Hz, 1H), 7.49-7.30(m, 7H), 7.12 (dd, J=8.1, 1.96 Hz, 1H), 6.91 (dd, J=8.4, 2.1 Hz, 1H),5.16 (s, 2H), 1.68 (s, 6H).

Part B

A mixture of5-{[(3-benzyloxy)phenylimino]methyl}-2,2-dimethyl-[1,3]-dioxane-4,6-dione(170.65 g, 0.483 mol) and DOWTHERM A (800 mL) heat transfer fluid washeated to 100° C. and then slowly added to a flask containing DOWTHERM A(1.3 liters (L), heated at 210° C.) heat transfer fluid over a period of40 minutes. During the addition, the reaction temperature was notallowed to fall below 207° C. Following the addition, the reaction wasstirred at 210° C. for one hour, and then allowed to cool to ambienttemperature. A precipitate formed, which was isolated by filtration,washed sequentially with diethyl ether (1.7 L) and acetone (0.5 L), anddried in an oven to provide 76.5 g of 7-benzyloxyquinolin-4-ol as a tanpowder. ¹H NMR (300 MHz, DMSO-d₆) δ 11.53 (s, 1H), 7.99 (dd, J=2.4, 7.4Hz, 1H), 7.79 (d, J=7.4 Hz, 1H), 7.50-7.32 (m, 5H), 7.00 (s, 1H), 6.98(dd, J=2.5, 7.4 Hz, 1H), 5.93 (d, J=7.5 Hz, 1H), 5.20 (s, 2H).

Part C

A mixture of 7-benzyloxyquinolin-4-ol (71.47 g, 0.2844 mol) andpropionic acid (700 mL) was heated to 125° C. with vigorous stirring.Nitric acid (23.11 mL of 16 molar (M)) was slowly added over a period of30 minutes while maintaining the reaction temperature between 121° C.and 125° C. After the addition, the reaction was stirred at 125° C. forone hour then allowed to cool to room temperature. The resulting solidwas isolated by filtration, washed with water, and dried in an oven for1.5 days to provide 69.13 g of 7-benzyloxy-3-nitroquinolin-4-ol as agrayish powder. ¹H NMR (300 MHz, DMSO-d₆) δ 12.77 (s, 1H), 9.12 (s, 1H),8.17 (dd, J=3.3, 6.3 Hz, 1H), 7.51-7.33 (m, 5H), 7.21-7.17 (m, 2H), 5.25(s, 2H). Material from a separate run was used in the next step.

Part D

A mixture of 7-benzyloxy-3-nitroquinolin-4-ol (10.67 g, 36.0 millimoles(mmol)) and 5% platinum on carbon (1.05 g) in N,N-dimethylformamide(DMF) (110 mL) was hydrogenated on a Parr apparatus. The mixture wasfiltered through CELITE filter agent. The CELITE filter agent was rinsedwith DMF (20 mL). The filtrate was cooled in an ice bath and acidifiedwith hydrogen chloride gas, resulting in the formation of areddish-brown solid. The solid was isolated by filtration, washed withacetone, and dried in a vacuum oven at 60° C. to provide 8.17 g of3-amino-7-benzyloxyquinolin-4-ol hydrochloride as a tan solid.

Part E

To a solution of the crude 3-amino-7-benzyloxyquinolin-4-olhydrochloride (8.03 g, 26.5 mmol) prepared in Part D and triethylamine(7.40 mL, 53 mmol) in dichloromethane at 0° C. was added butyrylchloride (2.75 mL, 26.5 mmol) dropwise. The solution was stirred at 0°C. for ten minutes, and then the cooling bath was removed. A solidformed that was isolated by filtration and washed with a small amount ofdichloromethane. The solid was triturated with water (75 mL) and wasisolated by filtration. The solid was rinsed sequentially with water anddiethyl ether and dried at 60° C. in a vacuum oven to provide 8.03 g ofN-(7-benzyloxy-4-hydroxyquinolin-3-yl)butyramide, containing a smallamount of triethylamine hydrochloride as determined by proton nuclearmagnetic resonance spectroscopy (¹H NMR) analysis.

Part F

Under a nitrogen atmosphere, a mixture of theN-(7-benzyloxy-4-hydroxyquinolin-3-yl)butyramide prepared in Part E(2.97 g, 8.83 mmol), phosphorus pentasulfide (1.96 g, 4.41 mmol), andpyridine was heated to reflux. The resulting solution was cooled and theexcess phosphorus pentasulfide was quenched slowly with 10% aqueoussodium carbonate (10 mL). The reaction mixture was partitioned betweenwater (40 mL) and dichloromethane (100 mL). The organic layer was washedwith 0.1 M aqueous hydrochloric acid (50 mL), dried over magnesiumsulfate, filtered and concentrated under reduced pressure to yield abrownish-yellow solid. The solid was recrystallized from heptane (40 mL,hot filtration). The crystals were isolated by filtration and washedwith cold heptane to provide 1.74 g of7-benzyloxy-2-propyl[1,3]thiazolo[4,5-c]quinoline as a light yellowsolid.

Part G

To a solution of 7-benzyloxy-2-propyl[1,3]thiazolo[4,5-c]quinoline (4.89g, 14.6 mmol) in dichloromethane (75 mL) at room temperature was added3-chloroperoxybenzoic acid (mCPBA) (5.82 g of 65% purity, 21.93 mmol) inportions. After one hour of stirring, the mixture was washed with 10%aqueous sodium carbonate (2×50 mL). The combined washings were extractedwith dichloromethane (50 mL), and the combined organic fractions werewashed with water (75 mL), dried over magnesium sulfate, filtered,concentrated under reduced pressure, and dried under high vacuum toyield 4.93 g of7-benzyloxy-5-oxido-2-propyl[1,3]thiazolo[4,5-c]quinoline as a lightyellow solid.

Part H

To a light orange solution of7-benzyloxy-5-oxido-2-propyl[1,3]thiazolo[4,5-c]quinoline (4.93 g, 14.1mmol) in dichloromethane (100 mL) at 0° C. was added trichloroacetylisocyanate (2.00 mL, 16.9 mmol). The solution was allowed to warm toroom temperature and was stirred for 20 hours. The solution wasconcentrated under reduced pressure, and the residue,N-(7-benzyloxy-2-propyl[1,3]thiazolo[4,5-c]quinolin-4-yl)-2,2,2-trichloroacetamide,was used without further manipulation in the next step.

Part I

To a stirred mixture ofN-(7-benzyloxy-2-propyl[1,3]thiazolo[4,5-c]quinolin-4-yl)-2,2,2-trichloroacetamide(6.96 g, 14.9 mmol) in methanol (100 mL) at room temperature was addedsodium methoxide (11.3 mL of a 25 weight % solution in methanol, 52.1mmol). After a few minutes a solution formed from which a solidprecipitated. The reaction mixture was concentrated under reducedpressure and further dried under vacuum. The resulting solid wassuspended in a minimal amount of methanol (50 mL) and was isolated byfiltration. The solid was washed with methanol to provide 3.93 g of7-benzyloxy-2-propyl[1,3]thiazolo[4,5-c]quinolin-4-amine as a lightyellow solid, mp 175-178° C. ¹H NMR (300 MHz, d₆-DMSO) δ 7.67 (d, J=8.7Hz, 1H), 7.49-7.29 (m, 5H), 7.10 (d, J=2.5 Hz, 1H), 6.96 (dd, J=8.7, 2.5Hz, 1H), 6.84 (s, 2H), 5.20 (s, 2H), 3.09 (t, J=7.8 Hz, 2H), 1.84(sextet, J=7.2 Hz, 2H), 0.99 (t, J=7.5 Hz, 3H); ¹³C NMR (75 MHz,d₆-DMSO) δ 169.1, 158.9, 152.4, 146.5, 139.4, 137.0, 136.0, 128.4,127.8, 127.6, 125.7, 113.3, 113.2, 107.8, 69.3, 35.1, 22.8, 13.5; MS(APCI) m/z 350.0 (M+H⁺).

Part J

Under a nitrogen atmosphere, a solution of hydrogen bromide in aceticacid (50 mL of 30% weight/weight (w/w)) was added to7-benzyloxy-2-propyl[1,3]thiazolo[4,5-c]quinolin-4-amine (3.55 g, 10.2mmol), and the reaction was heated at 65° C. for 30 minutes and thencooled to approximately 0° C. Aqueous sodium hydroxide (50% w/w) wasadded slowly to adjust the reaction mixture to pH 7. A light yellowsolid formed, which was isolated by filtration and air-dried to provide4-amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-ol acetic acid salt.

Part K

Under a nitrogen atmosphere, cesium carbonate (6.29 g, 19.3 mmol) wasadded to a suspension of the material from Part J (3.86 mmol) in DMF (20mL), and the reaction mixture was heated at 75° C. for 30 minutes.4-(2-Chloroethyl)morpholine hydrochloride (0.90 g, 4.8 mmol) was thenadded, and the mixture was stirred at 75° C. overnight. The solvent wasthen removed under reduced pressure at 65° C. The resulting solid waspartitioned between dichloromethane (100 mL) and water (100 mL). Theorganic layer was washed sequentially with water (50 mL) and brine (50mL), dried over magnesium sulfate, filtered, and concentrated underreduced pressure. The resulting dark brown solid was purified by columnchromatography using a HORIZON HPFC system (an automated, modularhigh-performance flash purification product available from Biotage, Inc,Charlottesville, Va., USA) (silica cartridge, eluting with 0 to 30%80:18:2 chloroform/methanol/concentrated ammonium hydroxide (CMA) inchloroform) to provide 0.48 g of a light yellow solid after drying underhigh vacuum. The solid was recrystallized from tert-butyl methyl ether(30 mL, hot filtration), and the crystals were washed with coldtert-butyl methyl ether and dried in a vacuum oven at 60° C. to provide0.32 g of7-(2-morpholin-4-ylethoxy)-2-propyl[1,3]thiazolo[4,5-c]quinolin-4-amineas light yellow needles, mp 122-125° C. ¹H NMR (500 MHz, d₆-DMSO) δ 7.65(d, J=8.5, 1H), 7.03 (d, J=2.5, 1H), 6.90 (dd, J=8.5, 2.5, 1H), 6.79 (s,2H), 4.17 (t, J=5.6, 2H), 3.58 (t, J=4.8, 4H), 3.11 (t, J=7.6, 2H), 2.72(t, J=5.6, 2H), 2.48 (m, 4H), 1.84 (sextet, J=7.5, 2H), 1.00 (t, J=7.5,3H); ¹³C NMR (125 Hz, d₆-DMSO) δ 169.0, 159.0, 152.3, 146.5, 139.3,136.0, 125.7, 113.1, 113.0, 107.3, 66.1, 65.4, 57.0, 53.6, 35.1, 22.7,13.4;

Anal. calcd for C₁₉H₂₄N₄O₂S: C, 61.27; H, 6.49; N, 15.04. Found: C,61.24; H, 6.54; N, 14.94.

Example 22-Propyl-7-(2-pyrrolidin-1-ylethoxy)[1,3]thiazolo[4,5-c]quinolin-4-amine

The method described in Part K of Example 1 was used to treat thematerial from Part J of Example 1 (5.40 mmol) in DMF (25 mL) with cesiumcarbonate (11.00 g, 33.75 mmol) and 1-(2-chloroethyl)pyrrolidinehydrochloride (1.15 g, 6.75 mmol) with the modification that thereaction was carried out at 70° C. instead of 75° C. The purificationmethods described in Part K of Example 1 were used to provide 0.33 g of2-propyl-7-(2-pyrrolidin-1-ylethoxy)[1,3]thiazolo[4,5-c]quinolin-4-amineas light yellow needles, mp 124-127° C. ¹H NMR (500 MHz, CDCl₃) δ 7.59(d, J=8.8, 1H), 7.17 (d, J=2.2, 1H), 6.98 (dd, J=8.9, 2.5, 11H), 5.51(s, 2H), 4.22 (t, J=5.7, 2H), 3.09 (t, J=7.6, 2H) 2.95 (t, J=6.0, 2H),2.63 (m, 4H), 1.93 (sextet, J=7.5, 2H), 1.80 (m, 4H), 1.07 (t, J=7.2,3H); ¹³C NMR (125 Hz, CDCl₃) δ 169.7, 159.8, 151.8, 146.2, 140.7, 136.4,125.6, 115.0, 114.3, 107.5, 67.2, 55.1, 54.7, 36.0, 23.5, 23.2, 13.7;

Anal. calcd for C₁₉H₂₄N₄OS: C, 64.02; H, 6.79; N, 15.72. Found: C,63.85; H, 6.65; N, 15.64.

Example 37-(2-Piperidin-1-ylethoxy)-2-propyl[1,3]thiazolo[4,5-c]quinolin-4-amine

The method described in Part K of Example 1 were used to treat thematerial from Part J of Example 1 (5.67 mmol) in DMF (25 mL) with cesiumcarbonate (9.24 g, 28.4 mmol) and 1-(2-chloroethyl)piperidinehydrochloride (1.30 g, 7.09 mmol) with the modification that thereaction was carried out at 70° C. instead of 75° C. The purificationmethods described in Part K of Example 1 were used, with themodification that chromatographic purification was carried out elutingwith 0 to 35% CMA in chloroform, to provide 0.41 g of7-(2-piperidin-1-ylethoxy)-2-propyl[1,3]thiazolo[4,5-c]quinolin-4-amineas light yellow needles, mp 141-143° C. ¹H NMR (500 MHz, d₆-DMSO) δ 7.65(d, J=8.9, 1H), 7.03 (d, J=2.5, 1H), 6.89 (dd, J=8.9, 2.2, 1H), 6.79 (s,2H), 4.14 (t, J=6.0, 2H), 3.10 (t, J=7.5, 2H), 2.67 (t, J=6.0, 2H), 2.43(m, 4H), 1.84 (sextet, J=7.5, 2H), 1.49 (quin, J=4.6, 4H), 1.36 (m 2H),1.00 (t, J=7.6, 3H); ¹³C NMR (125 Hz, d₆-DMSO) δ 169.0, 159.1, 152.4,146.5, 139.4, 136.0, 125.7, 113.1, 113.0, 107.3, 65.7, 57.3, 54.4, 35.1,25.6, 23.9, 22.7, 13.4;

Anal. calcd for C₂₀H₂₆N₄OS: C, 64.83; H, 7.07; N, 15.12. Found: C,64.52; H, 7.37; N, 14.80.

Example 4 tert-Butyl3-[(4-amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]propylcarbamate

Part A

A solution of 3-amino-1-propanol (14.88 g, 0.1981 mol) indichloromethane (130 mL) was cooled to approximately 0° C., and asolution of di-tert-butyl dicarbonate (46.70 g, 0.2140 mol) indichloromethane (100 mL) was added dropwise over a period of 45 minutes.Upon the completion of the addition, the resulting solution was washedsequentially with aqueous sodium carbonate (2×100 mL of 2 M), aceticacid (2×50 mL of 5% w/w), and brine (75 mL); dried over magnesiumsulfate; filtered; and concentrated under reduced pressure to provide39.02 g of tert-butyl 3-hydroxypropylcarbamate as a colorless oilcontaining some tert-butanol.

Part B

A mixture of tert-butyl 3-hydroxypropylcarbamate (19.36 g, 110.5 mmol),triphenylphosphine (34.76 g, 132.6 mmol), imidazole (10.53 g, 154.7mmol), diethyl ether (500 mL), and acetonitrile (150 mL) was cooled toapproximately 0° C., and iodine (36.45 g, 143.6 mmol) was added in oneportion. The reaction mixture was allowed to warm to room temperatureslowly and stirred overnight. A precipitate formed, which was removed byfiltration and washed with a small amount of diethyl ether. The filtratewas washed sequentially with water (2×500 mL), saturated aqueous sodiumthiosulfate (2×250 mL), water (250 mL), and brine (250 mL); dried overmagnesium sulfate; filtered; and concentrated under reduced pressure toprovide a mixture of a yellow oil and a white solid. The mixture wasdiluted with heptane (50 mL) and filtered to remove the solid, which waswashed with heptane (50 mL). The filtrate was concentrated under reducedpressure to provide an oil that was diluted with heptane (50 mL) andfiltered to remove a solid, which was washed with heptane (50 mL). Thefiltrate was concentrated under reduced pressure to provide 22.60 g oftert-butyl 3-iodopropylcarbamate as a yellow oil containing about 9 mol% triphenylphosphine oxide as determined by ¹H NMR.

Part C

To 7-benzyloxy-2-propyl[1,3]thiazolo[4,5-c]quinoline (prepared asdescribed in Part F of Example 1, 4.52 g, 13.5 mmol) was added hydrogenbromide (40 mL of a 45 wt. % solution in acetic acid). The resultingsolution was heated at 65° C. for 1.5 hours and then cooled in an icebath. Aqueous sodium hydroxide (50% w/w solution) was added slowly toadjust the solution to pH 7, and a light yellow solid formed. The solidwas isolated by filtration, dried, and then suspended in boiling ethanol(25 mL) for 5 minutes. The mixture was allowed to cool to roomtemperature, and a tan solid was isolated by filtration. The solid waswashed with cold ethanol and dried in a vacuum oven to yield 2.69 g of2-propyl[1,3]thiazolo[4,5-c]quinolin-7-ol. Material from a separate runwas used in the next step.

Part D

Under a nitrogen atmosphere, cesium carbonate (10.13 g, 31.07 mmol) wasadded to a suspension of 2-propyl[1,3]thiazolo[4,5-c]quinolin-7-ol (5.06g, 20.7 mmol) in DMF (110 mL), and the reaction mixture was heated at65° C. A solution of tert-butyl 3-iodopropylcarbamate (7.08 g, 24.8mmol) in DMF (20 mL) was added dropwise with stirring. The reactionmixture was stirred at 65° C. overnight. The solvent was then removedunder reduced pressure at 65° C. The resulting solid was partitionedbetween dichloromethane (250 mL) and water (250 mL). The organic layerwas washed sequentially with saturated aqueous sodium thiosulfate (100mL), water (100 mL), and brine (100 mL); dried over magnesium sulfate;filtered; and concentrated under reduced pressure. The resulting solidwas purified by column chromatography on silica gel (eluting with 0 to4% methanol in chloroform) to provide 5.36 g of tert-butyl3-[(2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]propylcarbamate as alight yellow solid.

Part E

The method described in Part G of Example 1 was used to treat tert-butyl3-[(2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]propylcarbamate (1.20g, 2.99 mmol) with mCPBA (1.19 g of 65% pure material, 4.49 mmol) indichloromethane (20 mL) with the modification that the reaction wasstirred overnight. tert-Butyl3-[(5-oxido-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]propylcarbamate(1.08 g) was obtained as a light yellow solid.

Part F

A solution of tert-butyl3-[(5-oxido-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]propylcarbamate(1.08 g, 2.59 mmol) in 1,2-dichloroethane (25 mL) was heated in a sealedtube to 65° C., and then ammonium hydroxide (5 mL of 30% solution) andp-toluenesulfonyl chloride (0.49 g, 2.8 mmol) were added. The reactionwas heated at 65° C. for 24 hours and then diluted with dichloromethane(50 mL). The resulting mixture was washed with aqueous sodium carbonate(2×50 mL of 2 M), and the combined washings were extracted withdichloromethane (2×50 mL). The combined organic layers were washedsequentially with water (50 mL) and brine (50 mL), dried over magnesiumsulfate, filtered, and concentrated under reduced pressure. Theresulting light brown solid was purified by column chromatography usinga HORIZON HPFC system (silica cartridge, eluting with 0 to 18% CMA inchloroform) to provide 0.72 g of a light yellow solid after drying underhigh vacuum. The solid was recrystallized from tert-butyl methyl ether(40 mL, hot filtration), and the crystals were washed with coldtert-butyl methyl ether and dried in a vacuum oven at 40° C. overnightto provide tert-butyl3-[(4-amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]propylcarbamateas off-white needles, mp 146-149° C. ¹H NMR (300 MHz, d₆-DMSO) δ 7.66(d, J=8.8, 1H), 7.01 (d, J=2.5, 1H), 6.90 (t, J=2.5, 1H), 6.88 (dd,J=9.0, 2.5, 1H), 6.77 (s, 2H), 4.05 (t, J=6.3, 2H), 3.11 (t, J=7.2, 2H),3.08 (t, J=3.4, 2H), 1.90-1.78 (m, 4H), 1.36 (s, 9H), 1.00 (t, J=7.5,3H); ¹³C NMR (75 MHz, d₆-DMSO) δ 169.0, 159.2, 155.6, 152.3, 146.5,139.4, 136.0, 126.6, 125.6, 113.1, 113.0, 107.2, 79.1, 77.5, 65.3, 36.9,35.1, 29.2, 28.2, 22.8, 13.4;

Anal. calcd for C₂₁H₂₈N₄O₃S: C, 60.55; H, 6.78; N, 13.45. Found: C,60.64; H, 6.82; N, 13.57.

Example 5N-{3-[(4-Amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]propyl}methanesulfonamide

Part A

A solution of hydrogen chloride in ethanol (2 mL of 4.25 M) was added toa suspension of tert-butyl3-[(4-amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]propylcarbamate(0.69 g, 1.66 mmol) in ethanol (15 mL), and the reaction was heated at80° C. for 30 minutes, allowed to cool to room temperature, and stirredovernight. The solvent was removed under reduced pressure, anddichloromethane (100 mL) was added. The resulting solution was washedwith water (100 mL). The aqueous fraction was made basic with theaddition of ammonium hydroxide, and the resulting solution was extractedwith dichloromethane (2×50 mL). The organic fractions were combined,washed with brine (75 mL), dried over magnesium sulfate, filtered, andconcentrated under reduced pressure to provide 0.58 g of7-(3-aminopropoxy)-2-propyl[1,3]thiazolo[4,5-c]quinolin-4-aminecontaining some impurities.

Part B

Under a nitrogen atmosphere, a suspension of the material from Part Aand triethylamine (0.51 mL, 3.7 mmol) in dichloromethane (25 mL) wascooled to approximately 0° C. Methanesulfonyl chloride (0.14 mL, 1.8mmol) was added dropwise, and the reaction was allowed to slowly warm toroom temperature and stirred overnight. An analysis by high-performanceliquid chromatography (HPLC) indicated that starting material remained.The solvent was removed under reduced pressure, and the residue wassuspended in chloroform (80 mL) with triethylamine (5 mL).Methanesulfonyl chloride (0.14 mL, 1.8 mmol) was added, and the reactionwas stirred at room temperature for 5.5 hours. The reaction wasmonitored by HPLC, and additional methanesulfonyl chloride (0.84 mL, 11mmol) was added over the course of four days. The reaction mixture waspartitioned between chloroform (50 mL) and water (100 mL). The organicfraction was washed with brine (2×50 mL), dried over magnesium sulfate,filtered, and concentrated under reduced pressure. The resulting lightyellow solid was purified by column chromatography using a HORIZON HPFCsystem (silica cartridge, eluting with 0 to 25% CMA in chloroform), andthe purified product was dried in a vacuum oven at 60° C. overnight toprovide 0.17 g ofN-{3-[(4-amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]propyl}methanesulfonamideas off-white needles, mp 168-171° C. ¹H NMR (300 MHz, d₆-DMSO) δ 7.66(d, J=8.7, 1H), 7.08 (t, J=5.9, 1H), 7.04 (d, J=2.5, 1H), 6.90 (dd,J=8.8, 2.5, 1H), 6.79 (s, 2H), 4.12 (t, J=6.2, 2H), 3.17-3.08 (m, 4H),2.90 (s, 3H), 1.93 (sextet, J=6.6, 2H), 1.84 (sextet, J=7.2, 2H), 1.00(t, J=7.5, 3H); ¹³C NMR (75 MHz, d₆-DMSO) δ 169.0, 159.1, 152.3, 146.5,139.3, 135.9, 125.6, 113.1, 107.3, 64.9, 39.4, 39.2, 35.0, 29.2, 22.7,13.4;

Anal. calcd for C₁₇H₂₂N₄O₃S₂: C, 51.76; H, 5.62; N, 14.20. Found: C,51.53; H, 5.37; N, 14.10.

Example 6N-{3-[(4-Amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]propyl}-5-(dimethylamino)naphthalene-1-sulfonamide

Pyridine (5 mL) and 4-dimethylaminopyridine (100 mg) were added to7-(3-aminopropoxy)-2-propyl[1,3]thiazolo[4,5-c]quinolin-4-amine (0.93 g,2.9 mmol, prepared according to the method described in Part A ofExample 5) in dichloromethane (40 mL).5-Dimethylamino-1-naphthalenesulfonyl chloride (0.95 g, 3.5 mmol, dansylchloride) were sequentially added to the mixture, and the resultingyellow solution was stirred overnight under a nitrogen atmosphere atroom temperature. An analysis by HPLC indicated the presence of startingmaterial, and additional dansyl chloride (240 mg) was added. Thereaction was stirred for two hours and then mixed with water (100 mL).The aqueous fraction was extracted with chloroform (2×100 mL), and thecombined organic fractions were washed with brine (100 mL), dried overmagnesium sulfate, filtered, and concentrated under reduced pressure.The resulting light yellow solid was purified by column chromatographyusing a HORIZON HPFC system (silica cartridge, eluting with 0 to 20% CMAin chloroform), and the purified product was dried under high vacuum toprovide 1.17 g ofN-{3-[(4-amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]propyl}-5-(dimethylamino)naphthalene-1-sulfonamideas a light yellow solid, mp 143-146° C. ¹H NMR (300 MHz, d₆-DMSO) δ 8.41(d, J=8.5, 1H), 8.30 (d, J=8.8, 1H), 8.10 (dd, J=7.2, 1.3, 1H), 7.98 (t,J=6.0, 1H), 7.60-7.55 (m, 2H), 7.20 (d, J=6.9, 1H), 6.88 (d, J=2.6, 1H),6.75 (s, 2H), 6.71 (dd, J=8.8, 2.5, 1H), 5.74 (s, 1H), 3.93 (t, J=6.0,2H), 3.11 (t, J=7.6, 2H), 2.98 (q, J=6.7, 2H), 2.77 (s, 6H), 1.88-1.78(m, 4H), 1.00 (t, J=7.5, 3H); ¹³C NMR (75 MHz, d₆-DMSO) δ 168.9, 158.9,152.3, 151.3, 146.4, 139.3, 135.9, 135.8, 129.4, 129.0, 128.3, 127.7,125.5, 123.4, 118.9, 115.0, 113.0, 112.9, 107.2, 64.6, 44.9, 39.3, 35.0,28.9, 22.7, 13.4.

Example 77-(2-Morpholin-4-yl-2-oxoethoxy)-2-propyl[1,3]thiazolo[4,5-c]quinolin-4-amine

Part A

A solution of bromoacetyl bromide (3.0 mL, 0.034 mol) in dichloromethane(240 mL) was cooled to −25° C. A solution of morpholine (9.0 mL, 0.10mol) in dichloromethane (20 mL) was slowly added over a period of onehour. After the addition was complete, the reaction was stirred at −25°C. for 15 minutes and allowed to warm to ambient temperature.Dichloromethane was added, and the resulting solution was washed withwater, 1N aqueous hydrogen chloride, and brine; dried over magnesiumsulfate; filtered; and concentrated under reduced pressure to provide4-(bromoacetyl)morpholine as a colorless oil.

Part B

Under a nitrogen atmosphere, cesium carbonate (4.44 g, 13.6 mmol) wasadded to a suspension of 2-propyl[1,3]thiazolo[4,5-c]quinolin-7-ol (2.22g, 9.09 mmol) in DMF (50 mL), and the reaction mixture was heated at 75°C. for 15 minutes. A solution of 4-(bromoacetyl)morpholine (2.26 g, 10.9mmol) in DMF (10 mL) was added dropwise with stirring. The reactionmixture was stirred at 75° C. for 2.25 hours. The solvent was thenremoved under reduced pressure at 75° C. The resulting solid waspartitioned between dichloromethane (250 mL) and water (250 mL). Theorganic layer was washed sequentially with water (100 mL) and brine (100mL), dried over magnesium sulfate, filtered, and concentrated underreduced pressure. The resulting solid was purified by columnchromatography using a HORIZON HPFC system (silica cartridge, elutingwith 0 to 20% CMA in chloroform), and the purified product was driedunder high vacuum to provide 2.84 g of7-(2-morpholin-4-yl-2-oxoethoxy)-2-propyl[1,3]thiazolo[4,5-c]quinolineas a light yellow solid. A portion of the product (0.37 g) wasrecrystallized from tert-butyl methyl ether (40 mL), and the crystalswere washed with cold tert-butyl methyl ether and dried in a vacuum ovenat 40° C. overnight to provide the following analytical data, mp133-136° C.

Anal. calcd for C₁₉H₂₁N₃O₃S: C, 61.44; H, 5.70; N, 11.31. Found: C,61.26; H, 5.74; N, 11.25.

Part C

The method described in Part G of Example 1 was used to treat7-(2-morpholin-4-yl-2-oxoethoxy)-2-propyl[1,3]thiazolo[4,5-c]quinoline(2.45 g, 6.60 mmol) with mCPBA (2.28 g of 65% pure material, 8.57 mmol)in dichloromethane (50 mL) to provide 2.58 g of7-(2-morpholin-4-yl-2-oxoethoxy)-5-oxido-2-propyl[1,3]thiazolo[4,5-c]quinolineas a light yellow solid.

Part D

The method described in Part F of Example 4 was used to treat7-(2-morpholin-4-yl-2-oxoethoxy)-5-oxido-2-propyl[1,3]thiazolo[4,5-c]quinoline(2.58 g, 6.66 mmol) with ammonium hydroxide (15 mL of 30%) andp-toluenesulfonyl chloride (1.26 g, 7.33 mmol) in 1,2-dichloroethane (60mL). The reaction was complete in four hours. The resulting light brownsolid was purified by column chromatography using a HORIZON HPFC system(silica cartridge, eluting with 0 to 5% CMA in chloroform followed by25% CMA in chloroform) to provide 1.88 g of a light yellow solid afterdrying under high vacuum. The solid was recrystallized from 2-propanol(175 mL), and the crystals were washed with cold 2-propanol and dried ina vacuum oven at 60° C. overnight to provide 1.54 g of7-(2-morpholin-4-yl-2-oxoethoxy)-2-propyl[1,3]thiazolo[4,5-c]quinolin-4-amineas white needles, mp 200-203° C. ¹H NMR (300 MHz, d₆-DMSO) δ 7.68 (d,J=8.7, 1H), 7.02 (d, J=2.5, 1H), 6.92 (dd, J=8.8, 2.5, 1H), 6.80 (s,2H), 4.93 (s, 2H), 3.61-3.47 (m, 8H), 3.11 (t, J=7.8, 2H), 1.84 (sextet,J=7.2, 2H), 1.02 (t, J=7.5, 3H); ¹³C NMR (75 MHz, d₆-DMSO) δ 169.1,165.9, 158.5, 152.4, 146.3, 139.3, 136.0, 125.6, 113.3, 113.0, 107.7,66.05, 65.9, 44.8, 41.6, 35.1, 22.7, 13.4;

Anal. calcd for C₁₉H₂₂N₄O₃S: C, 59.05; H, 5.74; N, 14.50. Found: C,59.08; H, 5.53; N, 14.20.

Example 8 tert-Butyl6-[(4-amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]hexylcarbamate

Part A

The methods described in Parts A and B of Example 4 were used to treat6-amino-1-hexanol (10.0 g, 85.3 mmol) with di-tert-butyl dicarbonate(20.1 g, 92.2 mmol) and treat the resulting product withtriphenylphosphine (26.14 g, 99.7 mmol), imidazole (7.92 g, 116.3 mmol),and iodine (27.41 g, 108.0 mmol). The resulting light yellow oil (19.36g) was purified by column chromatography (silica gel, eluting withdichloromethane) to provide 13.53 g of tert-butyl 6-iodohexylcarbamateas a light yellow oil.

Part B

Under a nitrogen atmosphere, cesium carbonate (2.58 g, 7.92 mmol) wasadded to a suspension of 2-propyl[1,3]thiazolo[4,5-c]quinolin-7-ol (1.29g, 5.28 mmol) in DMF (25 mL), and the reaction mixture was heated to 65°C. A solution of tert-butyl 6-iodohexylcarbamate (1.90 g, 5.81 mmol) inDMF (10 mL) was added dropwise with stirring. The reaction mixture wasstirred at 65° C. for 5.5 hours. The solvent was then removed underreduced pressure at 65° C. The resulting solid was partitioned betweendichloromethane (100 mL) and water (100 mL). The organic layer waswashed sequentially with saturated aqueous sodium thiosulfate (50 mL),water (50 mL), and brine (50 mL); dried over magnesium sulfate;filtered; and concentrated under reduced pressure. The resulting solidwas purified by column chromatography using a HORIZON HPFC system(silica cartridge, eluting with 0 to 6% CMA in chloroform), and thepurified product was dried under high vacuum to provide 1.79 g oftert-butyl6-[(2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]hexylcarbamate as alight yellow solid.

Part C

The method described in Part G of Example 1 was used to treat tert-butyl6-[(2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]hexylcarbamate (1.80g, 4.06 mmol) with mCPBA (1.62 g of 65% pure material, 6.09 mmol) indichloromethane (30 mL) with the modification that the reaction wasstirred for 2.5 hours. tert-Butyl6-[(5-oxido-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]hexylcarbamate(1.79 g) was obtained as a light yellow solid.

Part D

The method described in Part F of Example 4 was used to treat tert-butyl6-[(5-oxido-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]hexylcarbamate(1.79 g, 3.90 mmol) with ammonium hydroxide (8 mL of 30%) andp-toluenesulfonyl chloride (0.74 g, 4.3 mmol) in 1,2-dichloroethane (40mL). The reaction was stirred for one hour at 65° C., allowed to come toroom temperature, and stirred overnight. The purification methodsdescribed in Part F of Example 4 were used, with the modification thatchromatographic purification was carried out eluting with 0 to 15% CMAin chloroform, to provide 1.06 g of tert-butyl6-[(4-amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]hexylcarbamateas off-white needles, mp 136-139° C. ¹H NMR (300 MHz, d₆-DMSO) δ 7.64(d, J=8.7, 1H), 7.01 (d, J=2.5, 1H), 6.88 (dd, J=9.0, 2.5, 1H), 6.77 (m,3H), 4.03 (t, J=6.6, 2H), 3.11 (t, J=7.5, 2H), 2.90 (q, J=6.6, 2H),1.90-1.71 (m, 4H), 1.39-1.30 (m, 15H), 1.00 (t, J=7.1, 3H); ¹³C NMR (75MHz, d₆-DMSO) δ 168.9, 159.3, 155.5, 152.3, 146.5, 139.4, 135.9, 125.6,113.1, 113.0, 107.2, 77.2, 67.4, 35.1, 29.4, 28.6, 28.2, 26.0, 25.2,22.8, 13.4; Anal. calcd for C₂₄H₃₄N₄O₃S: C, 62.85; H, 7.47; N, 12.22.Found: C, 62.80; H, 7.36; N, 12.18.

Example 9N-{6-[(4-Amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]hexyl}methanesulfonamide

Part A

A solution of hydrogen chloride in ethanol (3 mL of 4.25 M) was added toa suspension of tert-butyl6-[(4-amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]hexylcarbamate(0.93 g, 2.0 mmol) in ethanol (20 mL), and the reaction was heated at80° C. for one hour, allowed to cool to room temperature, andconcentrated to dryness under reduced pressure. The residue waspartitioned between water (50 mL) and dichloromethane (30 mL) was added.The aqueous fraction was made basic with the addition of ammoniumhydroxide, and the resulting solution was extracted with dichloromethane(2×50 mL). The organic fractions were combined, washed with brine (75mL), dried over magnesium sulfate, filtered, and concentrated underreduced pressure to provide 0.73 g of7-[(6-aminohexyl)oxy]-2-propyl[1,3]thiazolo[4,5-c]quinolin-4-amine.

Part B

Under a nitrogen atmosphere, methanesulfonyl chloride (0.35 mL, 4.1mmol) was added dropwise to a suspension of7-[(6-aminohexyl)oxy]-2-propyl[1,3]thiazolo[4,5-c]quinolin-4-amine (0.73g, 2.0 mmol) and triethylamine (5 mL, 36 mmol) in chloroform (50 mL),and the reaction was stirred overnight. The work-up procedure describedin Part B of Example 5 was followed. The resulting light yellow solidwas purified by column chromatography using a HORIZON HPFC system(silica cartridge, eluting with 0 to 20% CMA in chloroform) to provide0.47 g of a light yellow solid after drying under high vacuum. The solidwas recrystallized from toluene (25 mL), and the crystals were washedwith cold toluene and dried in a vacuum oven at 60° C. overnight toprovide 0.32 g ofN-{6-[(4-amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]hexyl}methanesulfonamideas off-white needles, mp 138-134° C. ¹H NMR (300 MHz, d₆-DMSO) δ 7.64(d, J=8.7, 1H), 7.02 (d, J=2.5, 1H), 6.92 (t, J=5.9, 1H), 6.88 (dd,J=8.8, 2.5, 1H), 6.78 (s, 2H), 4.04 (t, J=6.4, 2H), 3.10 (t, J=7.5, 2H),2.92 (q, J=6.6, 2H), 2.86 (s, 3H), 1.90-1.70 (m, 4H) 1.53-1.33 (m, 6H),1.00 (t, J=7.5, 3H); ¹³C NMR (75 MHz, d₆-DMSO) δ 168.9, 159.3, 152.3,146.5, 139.4, 135.9, 125.6, 113.1, 113.0, 107.2, 67.4, 42.4, 39.2, 35.1,29.3, 28.5, 25.9, 25.2, 22.7, 13.4;

Anal. calcd for C₂₀H₂₈N₄O₃S₂: C, 55.02; H, 6.46; N, 12.83. Found: C,55.20; H, 6.80; N, 12.68.

Example 10 tert-Butyl2-{2-[(4-amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]ethoxy}ethylcarbamate

Part A

A solution of 2-(2-aminoethoxy)ethanol (15.0 g, 143 mmol) intetrahydrofuran (THF) (90 mL) was cooled to approximately 0° C., andaqueous sodium hydroxide (72 mL of 2 M) was added over a period of 20minutes. A solution of di-tert-butyl dicarbonate (31.1 g, 143 mmol) inTHF (90 mL) was then added over a period of 20 minutes. The reaction wasstirred for one hour at 0° C. and then allowed to warm to roomtemperature and stirred overnight. The THF was removed under reducedpressure, and the resulting aqueous mixture was adjusted to pH 3 withthe addition of 1 M sulfuric acid. The acidic mixture was extracted withethyl acetate (3×100 mL), and the combined extracts were washedsequentially with water (150 mL) and brine (150 mL), dried overmagnesium sulfate, filtered, and concentrated under reduced pressure toprovide 27.1 g of tert-butyl 2-(2-hydroxyethoxy)ethylcarbamate as acolorless oil. A portion of the oil (10.0 g, 48.7 mmol) was treated withtriphenylphosphine (15.33 g, 58.45 mmol), imidazole (4.64 g, 68.2 mmol),and iodine (16.01 g, 63.3 mmol) according to the method described inPart B of Example 4, with the modification that dichloromethane (325 mL)was used instead of diethyl ether and acetonitrile, to provide 7.82 g oftert-butyl 2-(2-iodoethoxy)ethylcarbamate containing a small amount oftriphenylphosphine oxide.

Part B

Under a nitrogen atmosphere, cesium carbonate (1.50 g, 4.61 mmol) wasadded to a suspension of 2-propyl[1,3]thiazolo[4,5-c]quinolin-7-ol (0.75g, 3.1 mmol) in DMF (15 mL), and the reaction mixture was heated at 75°C. for 30 minutes. A solution of tert-butyl2-(2-iodoethoxy)ethylcarbamate (1.93 g, 6.14 mmol) in DMF (5 mL) wasadded dropwise with stirring. The reaction mixture was stirred at 75° C.for 3.75 hours. The solvent was then removed under reduced pressure at65° C. The resulting solid was partitioned between dichloromethane (100mL) and water (100 mL). The organic layer was washed sequentially withwater (50 mL) and brine (50 mL), dried over magnesium sulfate; filtered,and concentrated under reduced pressure. The resulting dark brown solidwas purified by column chromatography using a HORIZON HPFC system(silica cartridge, eluting with 0 to 8% CMA in chloroform), and thepurified product was dried under high vacuum to provide 1.31 g oftert-butyl2-{2-[(2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]ethoxy}ethylcarbamateas a light yellow solid.

Part C

Under a nitrogen atmosphere, mCPBA (1.20 g, 4.30 mmol, 65% pure) wasadded in portions to a solution of tert-butyl2-{2-[(2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]ethoxy}ethylcarbamate(1.25 g, 2.90 mmol) in dichloromethane (75 mL), and the reaction wasstirred at room temperature for 1.75 hours, diluted with chloroform (100mL), and washed with 10% aqueous sodium carbonate (2×50 mL). The aqueouslayer was extracted with chloroform (50 mL), and the combined organicfractions were washed with water (75 mL), dried over magnesium sulfate,filtered, concentrated under reduced pressure, and dried under highvacuum to yield 1.23 g of tert-butyl2-{2-[(5-oxido-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]ethoxy}ethylcarbamateas a light yellow solid.

Part D

The method described in Part F of Example 4 was used to treat tert-butyl2-{2-[(5-oxido-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]ethoxy}ethylcarbamate(1.23 g, 2.75 mmol) with ammonium hydroxide (5 mL of 30%) andp-toluenesulfonyl chloride (0.58 g, 3.0 mmol) in 1,2-dichloroethane (25mL) with the modifications that the reaction was allowed to run for 16hours, and chloroform was used instead of dichloromethane in the work-upprocedure. The purification methods described in Part F of Example 4were used, with the modification that chromatographic purification wascarried out eluting with 0 to 20% CMA in chloroform, to provide 0.583 gof tert-butyl2-{2-[(4-amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]ethoxy}ethylcarbamateas light yellow needles, mp 111-113° C. ¹H NMR (300 MHz, d₆-DMSO) δ 7.66(d, J=8.8, 1H), 7.02 (d, J=2.5, 1H), 6.90 (dd, J=8.8, 2.5, 2H), 6.79 (s,2H), 4.17 (t, J=4.3, 2H), 3.76 (t, J=4.7, 2H), 3.46 (t, J=5.9, 2H), 3.09(m, 4H), 1.84 (sextet, J=7.5, 2H), 1.36 (s, 9H), 1.00 (t, J=7.5, 3H);¹³C NMR (75 MHz, d₆-DMSO) δ 169.1, 159.0, 155.6, 152.4, 146.5, 139.4,136.0, 125.7, 113.1, 107.2, 77.6, 69.3, 68.6, 67.1, 35.1, 28.2, 22.8,13.4;

Anal. calcd for C₂₂H₃₀N₄O₄S: C, 59.17; H, 6.77; N, 12.55. Found: C,58.88; H, 6.87; N, 12.64.

Example 11N-(2-{2-[(4-Amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]ethoxy}ethyl)methanesulfonamide

Part A

The method described in Part A of Example 9 was used to treat tert-butyl2-{2-[(4-amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]ethoxy}ethylcarbamate(0.74 g, 1.7 mmol) in ethanol (20 mL) with hydrogen chloride (3 mL of a4.25 M solution in ethanol) to provide 0.63 g of7-[2-(2-aminoethoxy)ethoxy]-2-propyl[1,3]thiazolo[4,5-c]quinolin-4-amineas a light yellow solid.

Part B

The method described in Part B of Example 9 was used to treat7-[2-(2-aminoethoxy)ethoxy]-2-propyl[1,3]thiazolo[4,5-c]quinolin-4-amine(0.63 g, 1.8 mmol) in chloroform (40 mL) with triethylamine (2.5 mL, 18mmol) and methanesulfonyl chloride (0.300 mL, 3.64 mmol); the reactionwas complete in 3.5 hours. The purification methods described in Part Bof Example 9 were used, with the modification that chromatographicpurification was carried out eluting with 0 to 30% CMA in chloroform, toprovide 0.40 g ofN-(2-{2-[(4-amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]ethoxy}ethyl)methanesulfonamideas off-white needles, mp 134-137° C. ¹H NMR (300 MHz, d₆-DMSO) δ 7.66(d, J=8.7, 1H), 7.07 (t, J=5.6, 1H), 7.03 (d, J=2.5, 1H), 6.90 (dd,J=8.7, 2.5, 1H), 6.80 (s, 2H), 4.19 (t, J=4.3, 2H), 3.79 (t, J=4.7, 2H),3.55 (t, J=5.9, 2H), 3.16-3.08 (m, 4H), 2.91 (s, 3H), 1.84 (sextet,J=7.5, 2H), 1.00 (t, J=7.5, 3H); ¹³C NMR (75 MHz, d₆-DMSO) δ 169.0,159.0, 152.4, 146.5, 139.3, 136.0, 125.7, 113.1, 113.0, 107.2, 69.8,68.7, 67.1, 42.3, 39.7, 35.1, 22.8, 13.4;

Anal. calcd for C₁₈H₂₄N₄O₄S₂: C, 50.92; H, 5.70; N, 13.20. Found: C,51.20; H, 5.48; N, 13.14.

Example 12 tert-Butyl2-[(4-amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]ethylcarbamate

Part A

The methods described in Parts A and B of Example 4 were used to treat2-amino-1-ethanol with di-tert-butyl dicarbonate and treat the resultingproduct (10.0 g, 62.0 mmol) with triphenylphosphine (19.52 g, 74.5mmol), imidazole (5.91 g, 86.9 mmol), and iodine (20.47 g, 80.65 mmol),with the modification that dichloromethane (400 mL) was used in thesecond step instead of diethyl ether and acetonitrile. The product,tert-butyl 2-iodoethylcarbamate (8.41 g) was obtained as a light yellowoil.

Part B

The method described in Part B of Example 10 was used to treat2-propyl[1,3]thiazolo[4,5-c]quinolin-7-ol (2.94 g, 12.0 mmol) in DMF (40mL) with cesium carbonate (5.88 g, 18.0 mmol) and a solution oftert-butyl 2-iodoethylcarbamate (4.89 g, 18.0 mmol) in DMF (10 mL). Thereaction was complete in 3.25 hours. The purification methods describedin Part B of Example 10 were used, with the modification thatchromatographic purification was carried out eluting with 0 to 4% CMA inchloroform, to provide 3.85 g of tert-butyl2-[(2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]ethylcarbamate as alight yellow solid.

Part C

The method described in Part C of Example 10 was used to treattert-butyl2-[(2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]ethylcarbamate (3.85g, 9.94 mmol) with mCPBA (2.57 g of 65% pure material, 14.9 mmol) indichloromethane to provide 4.01 g of tert-butyl2-[(5-oxido-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]ethylcarbamateas a light orange solid.

Part D

The method described in Part F of Example 4 was used to treat tert-butyl2-[(5-oxido-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]ethylcarbamate(4.01 g, 9.94 mmol) with ammonium hydroxide (17 mL of 30%) andp-toluenesulfonyl chloride (2.08 g, 10.9 mmol) in 1,2-dichloroethane (85mL). The reaction was complete in 4.5 hours. The purification methodsdescribed in Part F of Example 4 were used to provide 2.84 g oftert-butyl2-[(4-amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]ethylcarbamateas light yellow needles, mp 136-139° C. ¹H NMR (500 MHz, d₆-DMSO) δ 7.66(d, J=8.5, 11H), 7.02 (d, J=2.5, 1H), 7.01 (s, 1H), 6.89 (dd, J=8.8,2.5, 1H), 6.80 (s, 2H), 4.04 (t, J=5.8, 2H), 3.33 (q, J=5.7, 2H), 3.11(t, J=7.6, 2H), 1.84 (sextet, J=7.5, 2H), 1.38 (s, 9H), 1.00 (t, J=7.2,3H); ¹³C NMR (125 Hz, d₆-DMSO) δ 169.0, 159.0, 155.6, 152.4, 146.5,139.3, 136.0, 125.7, 131.1, 113.0, 107.3, 77.7, 66.4, 35.1, 28.2, 22.7,13.4;

Anal. calcd for C₂₀H₂₆N₄O₃S: C, 59.68; H, 6.51; N, 13.92. Found: C,59.59; H, 6.18; N, 13.88.

Example 13N-{2-[(4-Amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]ethyl}methanesulfonamide

Part A

A solution of hydrogen chloride in ethanol (15 mL of 2.2 M) was added toa suspension of tert-butyl2-[(4-amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]ethylcarbamate(2.57 g, 6.38 mmol) in ethanol (60 mL), and the reaction was heated at80° C. overnight. A precipitate began to form after about ten minutes.The solvent was removed under reduced pressure, and the resulting solidwas suspended in ethanol (25 mL), isolated by filtration, washed withethanol, and dried in a vacuum oven at 60° C. to provide 2.06 of7-(2-aminoethoxy)-2-propyl[1,3]thiazolo[4,5-c]quinolin-4-aminehydrochloride as a light yellow solid.

Part B

Under a nitrogen atmosphere, methanesulfonyl chloride (0.20 mL, 2.5mmol) was added dropwise to a solution of7-(2-aminoethoxy)-2-propyl[1,3]thiazolo[4,5-c]quinolin-4-aminehydrochloride (0.64 g, 1.9 mmol) and triethylamine (0.53 mL, 3.8 mmol)in chloroform (40 mL), and the reaction was stirred for 1.25 hours. Thework-up procedure described in Part B of Example 5 was followed. Theresulting light yellow solid was purified by column chromatography usinga HORIZON HPFC system (silica cartridge, eluting with 0 to 25% CMA inchloroform) to provide 0.73 g of an off-white solid after drying underhigh vacuum. The solid was recrystallized from propyl acetate (35 mL,hot filtration), and the crystals were washed with cold propyl acetateand dried in a vacuum oven at 60° C. overnight to provide 0.48 g ofN-{2-[(4-amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]ethyl}methanesulfonamideas light yellow needles, mp 148-151° C. ¹H NMR (300 MHz, d₆-DMSO) δ 7.68(d, J=8.7, 1H), 7.30 (t, J=6.0, 11H), 7.03 (d, J=2.5, 1H), 6.92 (dd,J=8.8, 2.5, 1H), 6.81 (s, 2H), 4.13 (t, J=5.6, 2H), 3.38 (q, J=5.6, 2H),3.11 (t, J=7.1, 2H), 2.95 (s, 3H), 1.84 (sextet, J=7.5, 2H), 1.00 (t,J=7.2, 3H); ¹³C NMR (75 Hz, d₆-DMSO) δ 169.1, 158.8, 152.4, 146.5,139.36, 136.0, 125.8, 113.2, 112.9, 107.3, 79.1, 66.9, 41.8, 35.1, 22.8,13.4;

Anal. calcd for C₁₆H₂₀N₄O₃S₂: C, 50.51; H, 5.30; N, 14.72. Found: C,50.78; H, 5.10; N, 14.67.

Example 14N,N′-Bis{2-[(4-amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]ethyl}urea

Under a nitrogen atmosphere, a suspension of7-(2-aminoethoxy)-2-propyl[1,3]thiazolo[4,5-c]quinolin-4-aminehydrochloride (0.60 g, 2.0 mmol) and carbonyldiimidazole (150 mg, 0.95mmol) in DMF was heated at 75° C. for four hours. Upon heating asolution formed, and a precipitate began to form after about 30 minutes.The reaction mixture was then combined with material from a smaller run,and the DMF was removed under reduced pressure at 65° C. Water (50 mL)was added to the residue, and the resulting solid was isolated byfiltration, washed with water, methanol (25 mL) and tert-butyl methylether (25 mL), and dried overnight in a vacuum oven at 80° C. A portionof the solid (250 mg) was suspended in warm DMF (25 mL) and filtered.The DMF was removed under reduced pressure at 65° C. The resulting solidwas suspended in chloroform (10 mL), isolated by filtration, washed withchloroform, and dried in a vacuum oven at 60° C. to provide 0.14 mg ofN,N-bis{2-[(4-amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]ethyl}ureaas a light yellow solid, mp 213-216° C. ¹H NMR (500 MHz, d₆-DMSO) δ 7.61(d, J=8.8, 2H), 7.03 (d, J=2.6, 2H), 6.89 (dd, J=8.5, 2.2, 2H), 6.81 (s,4H), 6.28 (t, J=5.3, 2H), 4.06 (t, J=5.6, 4H), 3.44 (q, J=5.4, 4H), 3.10(t, J=7.3, 4H), 1.84 (sextet, J=7.6, 4H), 1.00 (t, J=7.2, 6H); ¹³C NMR(125 Hz, d₆-DMSO) δ 169.0, 159.0, 158.0, 152.4, 146.5, 139.3, 136.0,125.7, 113.1, 112.9, 107.4, 67.4, 38.8, 35.1, 22.7, 13.4; HRMS (EI) m/zcalcd for C₃₁H₃₄N₈O₃S₂:631.2274; found: 631.2283.

Example 15Bis{2-[(4-amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]ethyl}ether

The method described in Part K of Example 1 was used to treat4-amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-ol acetic acid salt(prepared according to the method described in Part J of Example 1, 1.17g, 4.51 mmol) in DMF (10 mL) with cesium carbonate (3.27 g, 10.0 mmol)and 2-chloroethylether (288 mg, 2.01 mmol) with the modification thatthe reaction was carried out at 70° C. instead of 75° C. Thepurification methods described in Part K of Example 1 were used, withthe modification that chromatographic purification was carried outeluting with 0 to 25% CMA in chloroform. Following recrystallizationfrom tert-butyl methyl ether, the solid (0.38 g) was recrystallized from2-butanone (40 mL, hot filtration), and the crystals were washed withcold 2-butanone and dried in a vacuum oven at 60° C. to provide 0.21 gofbis{2-[(4-amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]ethyl}etheras light yellow needles, mp 186-189° C. ¹H NMR (500 MHz, d₆-DMSO) δ 7.63(d, J=8.7, 2H), 7.05 (d, J=2.5, 2H), 6.90 (dd, J=8.7, 2.5, 2H), 6.80 (s,4H), 4.22 (m, 4H), 3.88 (m, 4H), 3.10 (t, J=7.5, 4H), 1.84 (sextet,J=7.5, 4H), 1.00 (t, J=7.2, 6H); ¹³C NMR (125 Hz, d₆-DMSO) δ 169.0,159.0, 152.4, 146.5, 139.3, 136.0, 125.7, 113.1, 113.0, 107.3, 69.0,67.2, 35.1, 22.7, 13.4;

Anal. calcd for C₃₀H₃₂N₆O₃S₂ 0.5H₂O: C, 60.30; H, 5.56; N, 14.06. Found:C, 60.54; H, 5.48; N, 14.16.

Example 167-[2-(2-Chloroethoxy)ethoxy]-2-propyl[1,3]thiazolo[4,5-c]quinolin-4-amine

Part A

The method described in Part B of Example 10 was used to treat2-propyl[1,3]thiazolo[4,5-c]quinolin-7-ol (1.10 g, 4.50 mmol) in DMF (17mL) with cesium carbonate (1.76 g, 5.40 mmol) and a solution of1-chloro-2-(2-iodoethoxy)ethane (1.27 g, 5.40 mmol) in DMF (5 mL). Thereaction was complete in 2.75 hours. The purification methods describedin Part B of Example 10 were used to provide 1.18 g of7-[2-(2-chloroethoxy)ethoxy]-2-propyl[1,3]thiazolo[4,5-c]quinoline as alight yellow solid.

Part B

The method described in Part C of Example 10 was used to treat7-[2-(2-chloroethoxy)ethoxy]-2-propyl[1,3]thiazolo[4,5-c]quinoline (1.2g, 3.4 mmol) with mCPBA (1.36 g of 65% pure material, 5.13 mmol) indichloromethane (30 mL). The reaction was complete in 2.5 hours, and1.03 g of7-[2-(2-chloroethoxy)ethoxy]-5-oxido-2-propyl[1,3]thiazolo[4,5-c]quinolinewere obtained as a light orange solid.

Part C

The methods described in Parts H and I of Example 1 were used to treat7-[2-(2-chloroethoxy)ethoxy]-5-oxido-2-propyl[1,3]thiazolo[4,5-c]quinoline(1.03 g, 2.81 mmol) in dichloromethane (20 mL) with trichloroacetylisocyanate (0.40 mL) followed by sodium methoxide (2 mL of a 25% w/wsolution in methanol) in methanol (20 mL). The reaction with sodiummethoxide was complete within 45 minutes. The crude solid was purifiedby column chromatography using a HORIZON HPFC system (silica cartridge,eluting with 0 to 20% CMA in chloroform) to provide 0.93 g of a lightyellow solid after drying under high vacuum. The solid wasrecrystallized from tert-butyl methyl ether (35 mL, hot filtration), andthe crystals were washed with cold tert-butyl methyl ether and dried ina vacuum oven at 60° C. to provide 0.23 g of7-[2-(2-chloroethoxy)ethoxy]-2-propyl[1,3]thiazolo[4,5-c]quinolin-4-amineas a light yellow solid, mp 101-103° C. ¹H NMR (300 MHz, d₆-DMSO) δ 7.67(d, J=8.8, 1H), 7.03 (t, J=2.5, 1H), 6.91 (dd, J=8.7, 2.5, 1H), 6.79 (s,2H), 4.19 (t, J=4.3, 2H), 3.83 (t, J=4.7, 2H), 3.75 (s, 4H), 3.11 (t,J=7.8, 2H), 1.84 (sextet, J=7.5, 2H), 1.00 (t, J=7.5, 3H); ¹³C NMR (75MHz, d₆-DMSO) δ 169.5, 159.4, 152.8, 146.9, 139.8, 136.4, 126.1, 113.6,113.5, 107.7, 71.0, 69.2, 67.6, 43.9, 35.5, 23.1, 13.8;

Anal. calcd for C₁₇H₂₀N₃O₂SCl: C, 55.81; H, 5.51; N, 11.48. Found: C,55.74; H, 5.40; N, 11.29.

Examples 17-55

A reagent from the table below (1.1 equivalents, 0.11 mmol) was added toa test tube containing a solution of7-[2-(2-aminoethoxy)ethoxy]-2-propyl[1,3]thiazolo[4,5-c]quinolin-4-amine(prepared as described in Part A of Example 11, 35 mg, 0.10 mmol) andN,N-diisopropylethylamine (36 μL, 0.20 mmol) in N,N-dimethylacetamide(DMA) (1 mL). Each test tube was capped and placed on a shaker at roomtemperature four hours. Two drops of water were added to each test tube,and then the solvent was removed by vacuum centrifugation. The compoundswere purified by preparative high performance liquid chromatography(prep HPLC) using a Waters FractionLynx automated purification system.The prep HPLC fractions were analyzed using a Waters LC/TOF-MS, and theappropriate fractions were centrifuge evaporated to provide thetrifluoroacetate salt of the desired compound. Reversed phase prep HPLCwas performed with non-linear gradient elution from 5-95% B where A is0.05% trifluoroacetic acid/water and B is 0.05% trifluoroaceticacid/acetonitrile. Fractions were collected by mass-selectivetriggering. The table below shows the acid chloride, sulfonyl chloride,isocyanate, isothiocyanate, or carbamoyl chloride used for each example,the structure of the resulting compound, and the observed accurate massfor the isolated trifluoroacetate salt.

Examples 17-55

Measured Exam- Mass ple Reagent R (M + H) 17 None

347.1506 18 Acetyl chloride

389.1625 19 Propionylchloride

403.1834 20 Methylchloroformate

405.1556 21 Cyclopropane-carbonylchloride

415.1840 22 Butyryl chloride

417.1925 23 Cyclohexane-carbonylchloride

457.2274 24 Hydrocinnamoylchloride

479.2126 25 o-Anisoylchloride

481.1924 26 m-Anisoylchloride

481.1951 27 2-Chlorobenzoylchloride

485.1414 28 3-Chlorobenzoylchloride

485.1414 29 4-Chlorobenzoylchloride

485.1433 30 Nicotinoylchloridehydrochloride

452.1743 31 Picolinoylchloridehydrochloride

452.1712 32 Methanesulfonylchloride

425.1312 33 Ethanesulfonylchloride

439.1498 34 1-Propanesulfonylchloride

453.1635 35 Benzenesulfonylchloride

487.1468 36 1-Methyl-imidazole-4-sulfonyl chloride

491.1534 37 3-Cyanobenzene-sulfonyl chloride

512.1421 38 4-Cyanobenzene-sulfonyl chloride

512.1395 39 3-Methoxy-benzenesulfonylchloride

517.1613 40 4-Methoxy-benzenesulfonylchloride

517.1620 41 2-Chloro-benzenesulfonylchloride

521.1098 42 3-Chlorobenzene-sulfonyl chloride

521.1101 43 4-Chlorobenzene-sulfonyl chloride

521.1088 44 Cyclopropylisothiocyanate

446.1678 45 Cyclopentylisocyanate

458.2220 46 Cyclopropyl-methylisothiocyanate

460.1844 47 Phenyl isocyanate

466.1903 48 Cyclohexylisocyanate

472.2347 49 Phenylisothiocyanate

482.1696 50 2-Phenylethylisocyanate

494.2235 51 2-Methoxyphenylisocyanate

496.1979 52 3-Methoxyphenylisocyanate

496.2054 53 4-Methoxyphenylisocyanate

496.1994 54 N,N-Dimethyl-carbamoylchloride

418.1894 55 1-Piperidine-carbonylchloride

458.2241

Examples 56-101

An amine (0.15 mmol, 1.5 equivalents) from the table below was added toa test tube containing7-[2-(2-chloroethoxy)ethoxy]-2-propyl[1,3]thiazolo[4,5-c]quinolin-4-amine(prepared as described in Example 16, 37 mg, 0.10 mmol) and potassiumcarbonate (55 mg, 0.40 mmol) in DMA (1 mL). Each tube was capped andheated at 70° C. for 16 hours. An analysis by liquid chromatography/massspectrometry (LC/MS) indicated the presence of starting material forExamples 59 and 74; therefore, each reaction was heated at 85° C. forsix additional hours. Each reaction mixture was filtered, and the filtercake was washed with DMA (0.250 mL). The solvent was then removed fromthe filtrate by vacuum centrifugation. The compounds were purified usingthe method described in Examples 17-55. The table below shows the amineadded to each test tube, the structure of the resulting compound, andthe observed accurate mass for the isolated trifluoroacetate salt.

Examples 56-101

Ex- Measured am- Mass ple Reagent R (M + H) 56 None

366.1057 57 Pyrrolidine

401.2044 58 Piperidine

415.2173 59 Morpholine

417.1958 60 3-Methyl-piperidine

429.2318 61 4-Methyl-piperidine

429.2327 62 Hexamethylene-imine

429.2340 63 1-Methyl-piperazine

430.2311 64 3-Hydroxy-piperidine

431.2148 65 4-Hydroxy-piperidine

431.2130 66 Thiomorpholine

433.1730 67 N-Methylcyclo-hexylamine

443.2473 68 3-(Dimethyl-amino)pyrrolidine

444.2450 69 N,N′-Dimethyl-3-aminopyrrolidine

444.2456 70 1-Ethylpiperazine

444.2440 71 N-Methylhomo-piperazine

444.2461 72 2-Piperidine-methanol

445.2307 73 3-(Hydroxy-methyl)piperidine

445.2292 74 4-(Hydroxy-methyl)piperidine

445.2270 75 N-Methylbenzyl-amine

451.2189 76 3-Azabicyclo[3.2.2]nonane

455.2492 77 Nipecotamide

458.2202 78 (3S)-(−)-3-Acetamido-pyrrolidine

458.2253 79 1-Acetyl-piperazine

458.2245 80 1-Methyl-4-(methylamino)piperidine

458.2549 81 Nipecotic acid

459.2078 82 2-Piperidine-ethanol

459.2423 83 4-Piperidine-ethanol

459.2415 84 N-(2-Hydroxy-ethyl)piperazine

460.2406 85 1,2,3,4-Tetra-hydroiso-quinoline

463.2170 86 (R)-(+)-N-Methyl-1-phenyl-ethylamine

465.2357 87 (S)-(−)-N-Methyl-1-phenylethyl-amine

465.2369 88 N-Methylphenyl-ethylamine

465.2354 89 2-(2-Methyl-aminoethyl)pyridine

466.2282 90 Decahydroiso-quinoline

469.2622 91 Decahydro-quinoline

469.2635 92 1-(2-Methoxy-ethyl)piperazine

474.2541 93 alpha-(Methyl-aminomethyl)benzyl alcohol

481.2299 94 4-(1-Pyrrolidinyl)piperidine

484.2756 95 4-Phenyl-piperidine

491.2474 96 1-Phenyl-piperazine

492.2400 97 1-(2-Pyridyl)piperazine

493.2390 98 1-(4-Pyridyl)-piperazine

493.2389 99 1-(2-Pyrimdyl)piperazine

494.2330 100  4-Piperidino-piperidine

498.2913 101  1-Hydroxyethyl-ethoxypiperazine

504.2670

Example 1027-[2-(1,1-Dioxidoisothiazolidin-2-yl)ethoxy]-2-propyl[1,3]thiazolo[4,5-c]quinolin-4-amine

Under a nitrogen atmosphere, 3-chloropropanesulfonyl chloride (0.30 mL,2.4 mmol) was added dropwise to a solution of7-(2-aminoethoxy)-2-propyl[1,3]thiazolo[4,5-c]quinolin-4-aminehydrochloride (0.75 g, 2.2 mmol), prepared as described in Example 13Part A, and triethylamine (0.68 mL, 4.9 mmol) in chloroform (50 mL), andthe heterogeneous reaction was stirred overnight at room temperature. Ananalysis by HPLC indicated the presence of starting material, andadditional triethylamine (0.68 mL, 4.9 mmol) was added. The resultingsolution was stirred for 2.5 hours at room temperature, diluted withchloroform (100 mL), washed sequentially with water (50 mL) and brine(50 mL), dried over magnesium sulfate, filtered, and concentrated underreduced pressure to provide an orange solid. The solid was dissolved inDMF (15 mL), and the solution was heated to 50° C. under a nitrogenatmosphere, 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (0.42 mL, 2.8 mmol)was added in one portion, and the reaction was stirred at 50° C. for2.75 hours. The DMF was removed under reduced pressure at 65° C., andthe residue was partitioned between chloroform (100 mL) and water (100mL). The organic layer was separated and washed sequentially with water(50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography using a HORIZON HPFC system (silica cartridge,eluting with 0 to 25% CMA in chloroform) followed by recrystallizationfrom propyl acetate (25 mL for 0.35 g). The crystals were washed withcold propyl acetate and dried in a vacuum oven at 60° C. overnight toprovide 0.156 g of7-[2-(1,1-dioxidoisothiazolidin-2-yl)ethoxy]-2-propyl[1,3]thiazolo[4,5-c]quinolin-4-amineas a light yellow solid, mp 127-130° C.

¹H NMR (500 MHz, d₆-DMSO) δ 7.68 (d, J=8.9, 1H), 7.04 (d, J=2.2, 1H),6.91 (dd, J=8.8, 2.5, 1H), 6.81 (s, 2H), 4.22 (t, J=5.0, 2H), 3.37-3.28(m, 4H), 3.19 (t, J=7.6, 2H), 3.11 (t, J=7.6, 2H), 2.24 (quintet, J=7.0,2H), 1.84 (sextet, J=7.3, 2H), 1.00 (t, J=7.6, 3H);

¹³C NMR (125 Hz, d₆-DMSO) δ 169.1, 158.7, 152.4, 146.5, 139.3, 136.0,125.8, 113.2, 113.0, 107.4, 66.2, 47.7, 45.7, 43.8, 35.1, 22.8, 18.5,13.4;

Anal. calcd for C₁₈H₂₂N₄O₃S₂: C, 53.18; H, 5.46; N, 13.78. Found: C,53.27; H, 5.41; N, 13.66.

Example 103N-{2-[(4-Amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]ethyl}acrylamide

Under a nitrogen atmosphere, 3-chloropropionyl chloride (0.28 mL, 2.9mmol) was added dropwise to a solution of7-(2-aminoethoxy)-2-propyl[1,3]thiazolo[4,5-c]quinolin-4-aminehydrochloride (0.90 g, 2.7 mmol), prepared as described in Example 13Part A, and triethylamine (2.0 mL, 15 mmol) in chloroform (50 mL), andthe solution was stirred for 3.5 hours at room temperature. Theintermediate was isolated, dissolved in DMF, and treated with DBU (0.50mL, 3.3 mmol), as described in Example 102 with the modification thatthe reaction with DBU was heated for 5.25 hours. After the work-upprocedure, described in Example 102, the crude product was purified bycolumn chromatography using a HORIZON HPFC system (silica cartridge,eluting with 0 to 28% CMA in chloroform) followed by recrystallizationfrom acetonitrile (50 mL for 0.67 g). The crystals were washed with coldacetonitrile and dried in a vacuum oven at 60° C. overnight to provide0.426 g ofN-{2-[(4-amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]ethyl}acrylamideas a light yellow solid, mp 200-202° C.

¹H NMR (500 MHz, d₆-DMSO) δ 7.51 (d, J=8.9, 1H), 7.00 (d, J=2.5, 1H),6.86 (dd, J=8.9, 2.5, 1H), 6.18 (dd, J=17.0, 1.6, 1H), 6.09 (dd, J=17.0,10.7, 1H), 5.56 (dd, J=10.1, 1.9, 1H), 4.08 (t, J=5.3, 2H), 3.36-3.64(m, 5H), 3.00 (t, J=7.6, 2H), 1.83 (sextet, J=7.3, 2H), 0.97 (t, J=7.6,3H);

¹³C NMR (125 Hz, d₆-DMSO) δ 170.3, 166.4, 159.4, 151.8, 145.3, 140.9,136.0, 130.3, 126.5, 125.6, 114.0, 113.8, 107.1, 66.4, 38.7, 35.7, 23.0,13.3;

Anal. calcd for C₁₈H₂₀N₄O₂S: C, 60.65; H, 5.66; N, 15.72. Found: C,60.64; H, 5.60; N, 15.70.

Example 104N-{2-[(4-Amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]ethyl}pyrrolidin-2-one

Under a nitrogen atmosphere, 4-chlorobutyryl chloride (0.30 mL, 2.6mmol) was added dropwise to a solution of7-(2-aminoethoxy)-2-propyl[1,3]thiazolo[4,5-c]quinolin-4-aminehydrochloride (0.81 g, 2.4 mmol), prepared as described in Example 13Part A, and triethylamine (1.8 mL, 13 mmol) in chloroform (50 mL), andthe solution was stirred for 2.5 hours at room temperature. Theintermediate was isolated as an orange solid using the proceduredescribed in Example 102. A solution of the orange solid in DMF (15 mL)was slowly added to a mixture of sodium hydride (120 mg of a 60%dispersion in mineral oil, 3.0 mmol) in DMF (5 mL) that had been cooledto 0° C. The resulting mixture was stirred at 0° C. for 15 minutes,allowed to warm to room temperature, and stirred overnight. The DMF wasremoved under reduced pressure at 65° C., and the residue waspartitioned between chloroform (100 mL) and water (100 mL). The organiclayer was separated and washed with brine (50 mL), dried over magnesiumsulfate, filtered, and concentrated under reduced pressure. The crudeproduct was purified by column chromatography using a HORIZON HPFCsystem (silica cartridge, eluting with 0 to 25% CMA in chloroform)followed by recrystallization from acetonitrile (25 mL for 0.37 g). Thecrystals were washed with cold acetonitrile and dried in a vacuum ovenat 60° C. to provide 290 mg ofN-{2-[(4-amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]ethyl}pyrrolidin-2-oneas a light yellow solid, mp 163-166° C.

¹H NMR (500 MHz, d₆-DMSO) δ 7.67 (d, J=8.5, 1H), 7.04 (d, J=2.5, 1H),6.89 (dd, J=8.9, 2.5, 1H), 6.81 (s, 2H), 4.17 (t, J=5.7, 2H), 3.58 (t,J=5.4, 2H), 3.47 (t, J=6.9, 2H), 3.11 (t, J=7.5, 2H), 2.21 (t, J=7.8,2H), 1.94 (quintet, J=7.3, 2H), 1.84 (sextet, J=7.2, 2H), 1.00 (t,J=7.3, 3H);

¹³C NMR (125 Hz, d₆-DMSO) δ 174.1, 169.1, 158.8, 152.4, 146.5, 139.3,136.0, 125.7, 113.2, 113.0, 107.4, 65.5, 47.3, 41.4, 35.1, 30.2, 22.7,17.6, 13.4;

Anal. calcd for C₁₉H₂₂N₄O₂S: C, 61.60; H, 5.99; N, 15.12. Found: C,61.38; H, 6.18; N, 15.23.

Example 1052-[(4-Amino-2-ethyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]-1-thien-3-ylethanone

Part A

A Parr vessel was charged with 7-benzyloxy-3-nitroquinolin-7-ol (50.0 g,169 mmol), anhydrous DMF (500 mL), and 5% platinum on carbon (5.0 g).The vessel was placed on Parr apparatus, evacuated, and charged withhydrogen gas (approximately 45 psi, 3.1×10⁵ Pa). The reaction mixturewas shaken overnight and filtered to remove the catalyst. To theresulting dark colored solution was added concentrated aqueoushydrochloric acid (14 mL of 12 N solution). A precipitate formed, andthe reaction mixture was stirred over the weekend. The solid wascollected by vacuum filtration, washed with diethyl ether (100 mL), andair-dried overnight to provide 44 g of 3-amino-7-benzyloxyquinolin-4-olhydrochloride.

Part B

To a stirred solution of 3-amino-7-benzyloxyquinolin-4-ol hydrochloride(40.4 g, 133 mmol) and triethylamine (33.8 g, 334 mmol) indichloromethane (1000 mL) at room temperature, was slowly addedpropionyl chloride (13.6 g, 147 mmol). After the reaction was stirredfor six hours, water (250 mL) was added. The organic layer was separatedand concentrated to provide 41.5 g ofN-(7-benzyloxy-4-hydroxyquinolin-3-yl)propionamide as a pale tan,crystalline solid. MS (ACPI) m/z 323 (M+H)⁺.

Part C

To a stirred suspension of the material from Part B in pyridine (500 mL)was added phosphorus pentasulfide (28.6 g, 64.4 mmol). The reactionmixture was heated to reflux and became homogeneous and dark orange. Thereaction was heated at reflux overnight and then allowed to cool to roomtemperature. Aqueous sodium carbonate (50 mL of 10% w/w) was slowlyadded. The resulting mixture was partitioned between water (200 mL) anddichloromethane (700 mL). The aqueous layer was separated and extractedwith dichloromethane (3×100 mL). The organic fractions were combined andconcentrated under reduced pressure. The resulting tan solid was treatedwith boiling heptane (3×400 mL) and filtered. The heptane filtrates werecombined and concentrated to provide 15 g of7-benzyloxy-2-ethyl[1,3]thiazolo[4,5-c]quinoline as a pale yellowcrystalline solid. MS (ACPI) m/z=321 (M+H)⁺.

Part D

mCPBA (16.15 g of 50% pure material, 47 mmol) was slowly added in smallportions to a stirred solution of7-benzyloxy-2-ethyl[1,3]thiazolo[4,5-c]quinoline (15.0 g, 46.8 mmol) inchloroform (150 mL). The reaction was stirred at room temperatureovernight, washed with 10% aqueous sodium carbonate (2×50 mL), andconcentrated under reduced pressure to provide 15.4 g of7-benzyloxy-2-ethyl-5-oxido[1,3]thiazolo[4,5-c]quinoline as a light tansolid. MS (ACPI) m/z=337 (M+H)⁺.

Part E

Trichloroacetyl isocyanate (5.6 mL, 46.8 mmol) was slowly added to avigorously stirred pale orange solution of7-benzyloxy-2-ethyl-5-oxido[1,3]thiazolo[4,5-c]quinoline (15.0 g, 44.6mmol) in dichloromethane (200 mL) at room temperature. The solution wasmaintained at room temperature for 18 hours, and then concentratedammonium hydroxide solution (60 mL) was added. An off-white precipitateformed and was collected by vacuum filtration. Recrystallization fromacetonitrile provided 11.3 g of7-benzyloxy-2-ethyl[1,3]thiazolo[4,5-c]quinolin-4-amine as a whitecrystalline solid, mp 208-209° C. MS (APCI) m/z 336.1 (M+H)⁺; Anal.calcd for C₁₉H₁₇N₃OS: C, 68.03; H, 5.11; N, 12.53. Found: C, 67.45; H,4.83; N, 12.41.

Part F

Hydrogen bromide in acetic acid (40 mL of 45% w/w) was added to7-benzyloxy-2-ethyl[1,3]thiazolo[4,5-c]quinolin-4-amine (11.3 g, 33.7mmol), and the resulting solution was heated at 65° C. for two hours andthen cooled in an ice bath. Aqueous sodium hydroxide (50% w/w solution)was added slowly to adjust the solution to pH 7, and a pale yellow-greensolid formed. The solid was isolated by filtration and air-dried toprovide 8.4 g of 4-amino-2-ethyl[1,3]thiazolo[4,5-c]quinolin-7-ol. MS(APCI) m/z 246.0 (M+H)⁺.

Part G

A mixture of 4-amino-2-ethyl[1,3]thiazolo[4,5-c]quinolin-7-ol (245 mg,1.0 mmol), cesium carbonate (1.3 g, 4.0 mmol), and DMF (20 mL) wasstirred at 75° C. for ten minutes. 2-Bromo-1-(3-thienyl)-1-ethanone (225mg, 1.1 mmol) was added in portions over a period of 30 minutes. Thereaction mixture was stirred for two hours, allowed to cool, and dilutedwith water (250 mL). A precipitate formed. The mixture was stirred forone hour, and the solid was isolated by filtration. The isolated solidwas rinsed with water and then dried to provide a brown powder. Thismaterial was dissolved in dichloromethane and then purified by columnchromatography using a HORIZON HPFC system (silica cartridge, elutingwith a gradient of 0% to 20% CMA in chloroform over 700 mL and then with200 mL of 20% CMA in chloroform.) The resulting solid was recrystallizedfrom acetonitrile to provide 115 mg of2-[(4-amino-2-ethyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]-1-thien-3-ylethanoneas an off-white solid, mp 202.0-203.0° C.

MS (ESI) m/z 370 (M+H)⁺;

Anal. calcd for C₁₈H₁₅N₃O₂S₂: C, 58.52; H, 4.09; N, 11.37. Found C,58.44; H, 3.91; N, 11.32.

Example 1067-{3-[(4-Amino-2-ethyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]propoxy}-2-ethyl[1,3]thiazolo[4,5-c]quinolin-4-amine

Part A

A mixture of 4-amino-2-ethyl[1,3]thiazolo[4,5-c]quinolin-7-ol (1.00 g,4.08 mmol), cesium carbonate (5.30 g, 16.3 mmol), and DMF (40 mL) wasstirred at 50° C. for ten minutes. A solution of 1-bromo-3-chloropropane(705 mg, 4.48 mmol) in DMF (1.1 mL) was added in portions (0.05 mL)every seven minutes. After two hours, the reaction mixture was pouredinto water (225 mL). The mixture was stirred for 30 minutes and thenfiltered. The isolated solid was dried to provide 785 mg of7-(3-chloropropoxy)-2-ethyl[1,3]thiazolo[4,5-c]quinolin-4-amine as abrown solid.

Part B

A solution of7-(3-chloropropoxy)-2-ethyl[1,3]thiazolo[4,5-c]quinolin-4-amine (684 mg,2.12 mmol) in DMF (20 mL) was heated to 110° C. Sodium azide (151 mg,2.33 mol) was added in a single portion. After one hour the reactionmixture was poured into water (100 mL). The mixture was extracted withchloroform (3×100 mL). The combined extracts were concentrated underreduced pressure. The residue was dissolved in chloroform and purifiedby column chromatography using a HORIZON HPFC system (eluting with agradient of 0% to 20% CMA in chloroform over 700 mL and then with 20%CMA in chloroform for 600 mL). The major product isolated from thecolumn fractions was7-(3-azidopropoxy)-2-ethylthiazolo[4,5-c]quinolin-4-amine (400 mg). Asecond product isolated from the column was triturated with hotacetonitrile containing a small amount of methanol, and the mixture wasallowed to cool to room temperature. The resulting solid was isolated byfiltration to provide 75 mg of7-{3-[(4-amino-2-ethyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]propoxy}-2-ethyl[1,3]thiazolo[4,5-c]quinolin-4-amineas an off-white solid, mp 242.0-243.0° C.

MS (APCI) m/z 531 (M+H)⁺;

Anal. calcd for C₂₇H₂₆N₆O₂S₂: C, 61.11; H, 4.94; N, 15.84. Found C,60.90; H, 4.72; N, 15.71.

Example 1073-[(4-Amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]propan-1-ol

A mixture of 4-amino-2-ethyl[1,3]thiazolo[4,5-c]quinolin-7-ol aceticacid salt (see Parts A through J of Example 1) (0.640 g, 2.01 mmol),cesium carbonate (2.6 g, 8.0 mmol), and DMF (20 mL) was stirred at 75°C. for ten minutes. A solution of 1-bromo-3-chloropropane (0.350 g, 2.21mmol) in DMF (10 mL) was added dropwise over a period of 30 minutes. Thereaction was stirred at 75° C. for three hours, allowed to cool to roomtemperature, and poured into deionized water (200 mL). Brine (25 mL) wasadded, and a precipitate formed. The resulting mixture was stirred forone hour, and the solid was then collected by filtration. The solid wasstirred in a mixture of potassium carbonate and methanol overnight, andthe mixture was then filtered through a 0.2 micron TEFLON filter.Chloroform was added during the filtration. The filtrate wasconcentrated under reduced pressure, and the residue was partitionedbetween chloroform and water. The organic fraction was concentratedunder reduced pressure, and the residue was purified by columnchromatography using a HORIZON HPFC system (eluting with a gradient of0% to 20% CMA in chloroform over 900 mL and then with 20% CMA inchloroform for 500 mL). The resulting solid (400 mg) was recrystallizedfrom acetonitrile to provide 100 mg of3-[(4-amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]propan-1-ol asan off-white solid, mp 157.0-160.0° C.

MS (APCI) m/z 318 (M+H)⁺;

Anal. calcd for C₁₆H₁₉N₃O₂S: C, 60.55; H, 6.03; N, 13.24. Found C,60.32; H, 5.97; N, 13.33.

Examples 108-127 Part A

A solution of 4-hydroxypiperidine (10.00 g, 98.86 mmol), triethylamine(27.55 mL, 197.7 mmol), and dichloromethane (100 mL) was cooled toapproximately 0° C. under a nitrogen atmosphere. Di-tert-butyldicarbonate (23.73 g, 108.7 mmol) was added over a period of fiveminutes. The reaction was allowed to warm to room temperature slowly andstirred overnight and then added slowly with vigorous stirring to a cold(0° C.) solution of acetic acid (50 mL of 15% w/w in water). The organiclayer was separated and washed sequentially with 15% w/w acetic acid inwater (50 mL) and saturated aqueous sodium bicarbonate (3×33 mL), driedover sodium sulfate, filtered, and concentrated under reduced pressureto provide tert-butyl 4-hydroxypiperidine-1-carboxylate as a golden oilthat slowly solidified to an off-white solid.

Part B

A solution of diisopropyldiazodicarboxylate (4.63 mL, 23.5 mmol) wasadded dropwise over a period of two minutes to a solution of2-propyl[1,3]thiazolo[4,5-c]quinolin-7-ol (prepared as described inParts A through C of Example 4, 5.00 g, 20.5 mmol), tert-butyl4-hydroxypiperidine-1-carboxylate (4.74 g, 23.5 mmol), andtriphenylphosphine (6.16 g, 23.5 mmol) in tetrahydrofuran (150 mL) at 0°C. The resulting solution was allowed to warm to room temperature andstirred for 15 hours. A precipitate was present and was removed byfiltration. The filtrate was concentrated under reduced pressure. Thecrude product was purified by column chromatography using a HORIZON HPFCsystem (silica cartridge, eluting with 5% CMA in chloroform). Theresulting oil was treated with boiling tert-butyl methyl ether, and aprecipitate formed. The precipitate was removed by filtration, and thefiltrate was concentrated under reduced pressure. The residue wasrecrystallized from methanol to provide 3.76 g tert-butyl4-[(2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]piperidine-1-carboxylateas a white solid. The mother liquor was concentrated under reducedpressure to provide an additional 6.24 g of product containing sometriphenylphosphine oxide.

Part C

mCPBA (1.97 g of 70% pure material, 11 mmol) was added to a solution oftert-butyl4-[(2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]piperidine-1-carboxylate(3.76 g, 8.79 mmol), and the reaction was stirred at room temperaturefor 1.5 hours. An analysis by LC/MS indicated the presence of startingmaterial, and additional mCPBA (250 mg) was added. The reaction wasstirred at room temperature for an additional 1.5 hours; diluted withchloroform (20 mL); washed sequentially with aqueous sodium carbonate(20 mL of 10% w/w), water (20 mL), and brine (20 mL); dried over sodiumsulfate; filtered; and concentrated under reduced pressure to providetert-butyl4-[(5-oxido-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]piperidine-1-carboxylateas a light yellow solid.

Part D

A solution of the material from Part C in 1,2-dichloroethane (60 mL) washeated to 65° C. in a pressure vessel. Aqueous ammonium hydroxide (20 mLof 30% w/w) and p-toluenesulfonyl chloride (1.76 g, 9.23 mmol) werequickly added, and the vessel was sealed and heated at 70° C. for 15hours and allowed to cool to room temperature. The organic layer wasseparated and washed sequentially with aqueous sodium carbonate (20 mLof 10% w/w) and water (20 mL). The combined aqueous fractions wereextracted with chloroform (20 mL). The combined organic fractions werewashed with brine (25 mL), dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography using a HORIZON HPFC system (silica cartridge,eluting with 0% to 10% CMA in chloroform) to provide 2.07 g oftert-butyl4-[(4-amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]piperidine-1-carboxylateas a yellow solid.

Part E

A solution of hydrogen chloride (8 mL of 3.0 M in ethanol) was added toa solution of tert-butyl4-[(4-amino-2-propyl[1,3]thiazolo[4,5-c]quinolin-7-yl)oxy]piperidine-1-carboxylate(2.07 g, 4.68 mmol) in ethanol (16 mL), and the resulting solution washeated at 100° C. for 30 minutes. A precipitate formed, and the mixturewas allowed to cool to room temperature and diluted with diethyl ether(25 mL). The precipitate was collected by filtration, washed withdiethyl ether, and dried under vacuum overnight. The solid was suspendedin a small volume of water, and the suspension was cooled toapproximately 0° C. and adjusted to approximately pH 10 with theaddition of 50% w/w aqueous sodium hydroxide. A yellow precipitateformed and was collected by filtration, washed with water, and driedovernight under vacuum. The solid was purified by column chromatographyusing a HORIZON HPFC system (silica cartridge, eluting with 0% to 15%CMA in chloroform) followed by recrystallization from acetonitrile. Thecrystals were dried to provide7-(piperidin-4-yloxy)-2-propyl[1,3]thiazolo[4,5-c]quinolin-4-amine asyellow crystals.

¹H NMR (300 MHz, DMSO-d₆) δ 7.65 (d, J=8.7 Hz, 1H), 7.03 (d, J=2.4 Hz,1H), 6.90 (dd, J=8.7, 2.4 Hz, 1H), 6.77 (s, 2H), 4.54-4.46 (m, 1H), 3.12(t, J=7.3 Hz, 2H), 2.99-2.92 (m, 2H), 2.64-2.55 (m, 2H), 1.99-1.93 (m,3H), 1.85 (q, J=7.4 Hz, 2H), 1.54-1.42 (m, 2H), 1.01 (t, J=7.3 Hz, 3H);MS (APCI) m/z 343.16 (M+H)⁺.

Part F

A reagent from the table below (1.1 equivalents, 0.11 mmol) was added toa test tube containing a solution of7-(piperidin-4-yloxy)-2-propyl[1,3]thiazolo[4,5-c]quinolin-4-amine (34mg, 0.10 mmol) and N,N-diisopropylethylamine (35 μL, 0.20 mmol) in DMA(1 mL). Each test tube was capped and vortexed overnight. Water (100 μL)was added to each test tube, and then the solvent was removed by vacuumcentrifugation. The compounds were purified by prep HPLC according tothe method described in Examples 17-55. The table below shows the acidchloride, sulfonyl chloride, or isocyanate used for each example, thestructure of the resulting compound, and the observed accurate mass forthe isolated trifluoroacetate salt.

Examples 108-127

Measured Mass Example Reagent R (M + H) 108 None

343.1575 109 Acetyl chloride

385.1675 110 Propionyl chloride

399.1830 111 Cyclopropanecarbonylchloride

411.1852 112 Butyryl chloride

413.1994 113 Isobutyryl chloride

413.1981 114 Cyclopentanecarbonylchloride

439.2160 115 Cyclohexanecarbonylchloride

453.2302 116 Ethanesulfonylchloride

435.1503 117 1-Propanesulfonylchloride

449.1667 118 Isopropylsulfonylchloride

449.1693 119 1-Butanesulfonylchloride

463.1841 120 Methyl isocyanate

400.1782 121 Ethyl isocyanate

414.1935 122 Isopropyl isocyanate

428.2093 123 n-Propyl isocyanate

428.2105 124 Cyclopropylisothiocyanate

442.1723 125 Cyclopentylisocyanate

454.2264 126 Cyclohexyl isocyanate

468.2426 127 4-Morpholinylcarbonylchloride

456.2072

Examples 128-148

A reagent from the table below (1.1 equivalents, 0.11 mmol) was added toa test tube containing a solution of7-(2-aminoethoxy)-2-propyl[1,3]thiazolo[4,5-c]quinolin-4-aminehydrochloride, prepared as described in Example 13, Part A, (33.3 mg,0.10 mmol) and N,N-diisopropylethylamine (85 μL, 0.49 mmol) in DMA (1mL). Each test tube was capped and vortexed overnight. Water (two drops)was added to each test tube, and then the solvent was removed by vacuumcentrifugation. The compounds were purified by prep HPLC according tothe method described in Examples 17-55. The table below shows the acidchloride, sulfonyl chloride, or isocyanate used for each example, thestructure of the resulting compound, and the observed accurate mass forthe isolated trifluoroacetate salt.

Examples 128-148

Measured Mass Example Reagent R (M + H) 128 None

303.1298 129 Cyclopropane-carbonyl chloride

371.1510 130 Isobutyrylchloride

373.1663 131 Cyclopentane-carbonyl chloride

399.1880 132 Benzoyl chloride

407.1519 133 Isonicotinoylchloridehydrochloride

408.1518 134 Nicotinoyl chloridehydrochloride

408.1521 135 Methanesulfonylchloride

381.1058 136 Ethanesulfonylchloride

395.1172 137 Dimethylsulfamoylchloride

410.1331 138 Benzenesulfonylchloride

443.1214 139 1-Methylimidazole-4-sulfonyl chloride

447.1289 140 2,2,2-Trifluoro-ethanesulfonylchloride

449.0932 141 n-Propyl isocyanate

388.1840 142 Cyclopentylisocyanate

414.1980 143 Phenyl isocyanate

422.1646 144 Cyclohexylisocyanate

428.2161 145 N,N-Dimethyl-carbamoyl chloride

374.1687 146 1-Pyrrolidine-carbonyl chloride

400.1770 147 1-Piperidine-carbonyl chloride

414.1926 148 4-Morpholinyl-carbonyl chloride

416.1797

Examples 149-189

A phenol (0.165 mmol, 1.5 equivalents) from the table below was added toa test tube containing7-[2-(2-chloroethoxy)ethoxy]-2-propyl[1,3]thiazolo[4,5-c]quinolin-4-amine(prepared as described in Example 16, 40.3 mg, 0.11 mmol) and potassiumcarbonate (55 mg, 0.40 mmol) in DMA (1 mL). Each tube was capped andheated at 85° C. overnight. Each reaction mixture was filtered, and thefilter cake was washed with DMA (0.200 mL). The solvent was then removedfrom the filtrate by vacuum centrifugation. The compounds were purifiedusing the method described in Examples 17-55. The table below shows thephenol added to each test tube, the structure of the resulting compound,and the observed accurate mass for the isolated trifluoroacetate salt.

Examples 149-189

Measured Mass Example Reagent R (M + H)  16 None

366.1035 149 Phenol

424.1713 150 m-Cresol

438.1844 151 o-Cresol

438.1863 152 p-Cresol

438.1847 153 2-Fluorophenol

442.1598 154 3-Fluorophenol

442.1601 155 4-Fluorophenol

442.1590 156 2-Cyanophenol

449.1609 157 3-Cyanophenol

449.1630 158 4-Cyanophenol

449.1649 159 2,3-Dimethylphenol

452.2024 160 2,4-Dimethylphenol

452.2026 161 2,5-Dimethylphenol

452.1971 162 3,4-Dimethylphenol

452.1993 163 3-Methoxyphenol

454.1823 164 4-Methoxyphenol

454.1813 165 2-Chlorophenol

458.1309 166 3-Chlorophenol

458.1305 167 4-Chlorophenol

458.1325 168 4′-Hydroxy-acetophenone

466.1804 169 3′-Hydroxy-acetophenone

466.1821 170 4-Hydroxy-benzamide

467.1742 171 Salicylamide

467.1720 172 2-Nitrophenol

469.1570 173 3-Nitrophenol

469.1559 174 4-Nitrophenol

469.1566 175 (2-Hydroxy)thioanisole

470.1526 176 4-(Methylmercapto)phenol

470.1615 177 3-tert-Butyl-phenol

480.2295 178 2-Acetamidophenol

481.1928 179 3-Acetamidophenol

481.1924 180 4-Acetamidophenol

481.1940 181 Methyl 3-hydroxybenzoate

482.1783 182 2-Isopropoxyphenol

482.2131 183 2-Hydroxybenzo-trifluoride

492.1588 184 3-Hydroxybenzo-trifluoride

492.1577 185 4-Hydroxybenzo-trifluoride

492.1598 186 2,3-Dichlorophenol

492.0910 187 2,4-Dichlorophenol

492.0929 188 2,5-Dichlorophenol

492.0930 189 4-Hydroxybenzene-sulfonamide

503.1436

Exemplary Compounds

Certain exemplary compounds, including some of those described above inthe Examples, have the following Formula (IId) and the following Z,R_(3d), and R₂, substituents, wherein each line of the table is matchedwith Formula IId to represent a specific embodiment of the invention.

IId

Z R_(3d) R₂ —CH₂CH₂— (methylsulfonyl)amino ethyl —CH₂CH₂—(methylsulfonyl)amino propyl —CH₂CH₂— (methylsulfonyl)amino butyl—CH₂CH₂— (methylsulfonyl)amino 2-methoxyethyl —CH₂CH₂—(methylsulfonyl)amino ethoxymethyl —CH₂CH₂— pyrrolidin-1-yl ethyl—CH₂CH₂— pyrrolidin-1-yl propyl —CH₂CH₂— pyrrolidin-1-yl butyl —CH₂CH₂—pyrrolidin-1-yl 2-methoxyethyl —CH₂CH₂— pyrrolidin-1-yl ethoxymethyl—CH₂CH₂— morpholin-4-yl ethyl —CH₂CH₂— morpholin-4-yl propyl —CH₂CH₂—morpholin-4-yl butyl —CH₂CH₂— morpholin-4-yl 2-methoxyethyl —CH₂CH₂—morpholin-4-yl ethoxymethyl —CH₂CH₂— piperidin-1-yl ethyl —CH₂CH₂—piperidin-1-yl propyl —CH₂CH₂— piperidin-1-yl butyl —CH₂CH₂—piperidin-1-yl 2-methoxyethyl —CH₂CH₂— piperidin-1-yl ethoxymethyl—CH₂CH₂— azepan-1-yl ethyl —CH₂CH₂— azepan-1-yl propyl —CH₂CH₂—azepan-1-yl butyl —CH₂CH₂— azepan-1-yl 2-methoxyethyl —CH₂CH₂—azepan-1-yl ethoxymethyl —CH₂CH₂— 4-ethylpiperazin-1-yl ethyl —CH₂CH₂—4-ethylpiperazin-1-yl propyl —CH₂CH₂— 4-ethylpiperazin-1-yl butyl—CH₂CH₂— 4-ethylpiperazin-1-yl 2-methoxyethyl —CH₂CH₂—4-ethylpiperazin-1-yl ethoxymethyl —CH₂CH₂— 4-acetylpiperazin-1-yl ethyl—CH₂CH₂— 4-acetylpiperazin-1-yl propyl —CH₂CH₂— 4-acetylpiperazin-1-ylbutyl —CH₂CH₂— 4-acetylpiperazin-1-yl 2-methoxyethyl —CH₂CH₂—4-acetylpiperazin-1-yl ethoxymethyl —CH₂CH₂—4-(2-hydroxyethyl)piperazin-1-yl ethyl —CH₂CH₂—4-(2-hydroxyethyl)piperazin-1-yl propyl —CH₂CH₂—4-(2-hydroxethyl)piperazin-1-yl butyl —CH₂CH₂—4-(2-hydroxyethyl)piperazin-1-yl 2-methoxyethyl —CH₂CH₂—4-(2-hydroxyethyl)piperazin-1-yl ethoxymethyl —CH₂CH₂—3,4-dihydroisoquinolin-2(1H)-yl ethyl —CH₂CH₂—3,4-dihydroisoquinolin-2(1H)-yl propyl —CH₂CH₂—3,4-dihydroisoquinolin-2(1H)-yl butyl —CH₂CH₂—3,4-dihydroisoquinolin-2(1H)-yl 2-methoxyethyl —CH₂CH₂—3,4-dihydroisoquinolin-2(1H)-yl ethoxymethyl —CH₂CH₂—4-methyl-1,4-diazepan-1-yl ethyl —CH₂CH₂— 4-methyl-1,4-diazepan-1-ylpropyl —CH₂CH₂— 4-methyl-1,4-diazepan-1-yl butyl —CH₂CH₂—4-methyl-1,4-diazepan-1-yl 2-methoxyethyl —CH₂CH₂—4-methyl-1,4-diazepan-1-yl ethoxymethyl —CH₂CH₂—4-pyrimidin-2-ylpiperazin-1-yl ethyl —CH₂CH₂—4-pyrimidin-2-ylpiperazin-1-yl propyl —CH₂CH₂—4-pyrimidin-2-ylpiperazin-1-yl butyl —CH₂CH₂—4-pyrimidin-2-ylpiperazin-1-yl 2-methoxyethyl —CH₂CH₂—4-pyrimidin-2-ylpiperazin-1-yl ethoxymethyl —CH₂CH₂CH₂—(methylsulfonyl)amino ethyl —CH₂CH₂CH₂— (methylsulfonyl)amino propyl—CH₂CH₂CH₂— (methylsulfonyl)amino butyl —CH₂CH₂CH₂—(methylsulfonyl)amino 2-methoxyethyl —CH₂CH₂CH₂— (methyl sulfonyl)aminoethoxymethyl —CH₂CH₂CH₂— pyrrolidin-1-yl ethyl —CH₂CH₂CH₂—pyrrolidin-1-yl propyl —CH₂CH₂CH₂— pyrrolidin-1-yl butyl —CH₂CH₂CH₂—pyrrolidin-1-yl 2-methoxyethyl —CH₂CH₂CH₂— pyrrolidin-1-yl ethoxymethyl—CH₂CH₂CH₂— morpholin-4-yl ethyl —CH₂CH₂CH₂— morpholin-4-yl propyl—CH₂CH₂CH₂— morpholin-4-yl butyl —CH₂CH₂CH₂— morpholin-4-yl2-methoxyethyl —CH₂CH₂CH₂— morpholin-4-yl ethoxymethyl —CH₂CH₂CH₂—piperidin-1-yl ethyl —CH₂CH₂CH₂— piperidin-1-yl propyl —CH₂CH₂CH₂—piperidin-1-yl butyl —CH₂CH₂CH₂— piperidin-1-yl 2-methoxyethyl—CH₂CH₂CH₂— piperidin-1-yl ethoxymethyl —CH₂CH₂CH₂— azepan-1-yl ethyl—CH₂CH₂CH₂— azepan-1-yl propyl —CH₂CH₂CH₂— azepan-1-yl butyl —CH₂CH₂CH₂—azepan-1 -yl 2-methoxyethyl —CH₂CH₂CH₂— azepan-1-yl ethoxymethyl—CH₂CH₂CH₂— 4-ethylpiperazin-1-yl ethyl —CH₂CH₂CH₂—4-ethylpiperazin-1-yl propyl —CH₂CH₂CH₂— 4-ethylpiperazin-1-yl butyl—CH₂CH₂CH₂— 4-ethylpiperazin-1-yl 2-methoxyethyl —CH₂CH₂CH₂—4-ethylpiperazin-1-yl ethoxymethyl —CH₂CH₂CH₂— 4-acetylpiperazin-1-ylethyl —CH₂CH₂CH₂— 4-acetylpiperazin-1-yl propyl —CH₂CH₂CH₂—4-acetylpiperazin-1-yl butyl —CH₂CH₂CH₂— 4-acetylpiperazin-1-yl2-methoxyethyl —CH₂CH₂CH₂— 4-acetylpiperazin-1-yl ethoxymethyl—CH₂CH₂CH₂— 4-(2-hydroxyethyl)piperazin-1-yl ethyl —CH₂CH₂CH₂—4-(2-hydroxyethyl)piperazin-1-yl propyl —CH₂CH₂CH₂—4-(2-hydroxethyl)piperazin-1-yl butyl —CH₂CH₂CH₂—4-(2-hydroxyethyl)piperazin-1-yl 2-methoxyethyl —CH₂CH₂CH₂—4-(2-hydroxyethyl)piperazin-1-yl ethoxymethyl —CH₂CH₂CH₂—3,4-dihydroisoquinolin-2(1H)-yl ethyl —CH₂CH₂CH₂—3,4-dihydroisoquinolin-2(1H)-yl propyl —CH₂CH₂CH₂—3,4-dihydroisoquinolin-2(1H)-yl butyl —CH₂CH₂CH₂—3,4-dihydroisoquinolin-2(1H)-yl 2-methoxyethyl —CH₂CH₂CH₂—3,4-dihydroisoquinolin-2(1H)-yl ethoxymethyl —CH₂CH₂CH₂—4-methyl-1,4-diazepan-1-yl ethyl —CH₂CH₂CH₂— 4-methyl-1,4-diazepan-1-ylpropyl —CH₂CH₂CH₂— 4-methyl-1,4-diazepan-1-yl butyl —CH₂CH₂CH₂—4-methyl-1,4-diazepan-1-yl 2-methoxyethyl —CH₂CH₂CH₂—4-methyl-1,4-diazepan-1-yl ethoxymethyl —CH₂CH₂CH₂—4-pyrimidin-2-ylpiperazin-1-yl ethyl —CH₂CH₂CH₂—4-pyrimidin-2-ylpiperazin-1-yl propyl —CH₂CH₂CH₂—4-pyrimidin-2-ylpiperazin-1-yl butyl —CH₂CH₂CH₂—4-pyrimidin-2-ylpiperazin-1-yl 2-methoxyethyl —CH₂CH₂CH₂—4-pyrimidin-2-ylpiperazin-1-yl ethoxymethyl —CH₂CH₂CH₂CH₂—(methylsulfonyl)amino ethyl —CH₂CH₂CH₂CH₂— (methylsulfonyl)amino propyl—CH₂CH₂CH₂CH₂— (methylsulfonyl)amino butyl —CH₂CH₂CH₂CH₂—(methylsulfonyl)amino 2-methoxyethyl —CH₂CH₂CH₂CH₂—(methylsulfonyl)amino ethoxymethyl —CH₂CH₂CH₂CH₂— pyrrolidin-1-yl ethyl—CH₂CH₂CH₂CH₂— pyrrolidin-1-yl propyl —CH₂CH₂CH₂CH₂— pyrrolidin-1-ylbutyl —CH₂CH₂CH₂CH₂— pyrrolidin-1-yl 2-methoxyethyl —CH₂CH₂CH₂CH₂—pyrrolidin-1-yl ethoxymethyl —CH₂CH₂CH₂CH₂— morpholin-4-yl ethyl—CH₂CH₂CH₂CH₂— morpholin-4-yl propyl —CH₂CH₂CH₂CH₂— morpholin-4-yl butyl—CH₂CH₂CH₂CH₂— morpholin-4-yl 2-methoxyethyl —CH₂CH₂CH₂CH₂—morpholin-4-yl ethoxymethyl —CH₂CH₂CH₂CH₂— piperidin-1-yl ethyl—CH₂CH₂CH₂CH₂— piperidin-1-yl propyl —CH₂CH₂CH₂CH₂— piperidin-1-yl butyl—CH₂CH₂CH₂CH₂— piperidin-1-yl 2-methoxyethyl —CH₂CH₂CH₂CH₂—piperidin-1-yl ethoxymethyl —CH₂CH₂CH₂CH₂— azepan-1-yl ethyl—CH₂CH₂CH₂CH₂— azepan-1-yl propyl —CH₂CH₂CH₂CH₂— azepan-1-yl butyl—CH₂CH₂CH₂CH₂— azepan-1-yl 2-methoxyethyl —CH₂CH₂CH₂CH₂— azepan-1-ylethoxymethyl —CH₂CH₂CH₂CH₂— 4-ethylpiperazin-1-yl ethyl —CH₂CH₂CH₂CH₂—4-ethylpiperazin-1-yl propyl —CH₂CH₂CH₂CH₂— 4-ethylpiperazin-1-yl butyl—CH₂CH₂CH₂CH₂— 4-ethylpiperazin-1-yl 2-methoxyethyl —CH₂CH₂CH₂CH₂—4-ethylpiperazin-1-yl ethoxymethyl —CH₂CH₂CH₂CH₂— 4-acetylpiperazin-1-ylethyl —CH₂CH₂CH₂CH₂— 4-acetylpiperazin-1-yl propyl —CH₂CH₂CH₂CH₂—4-acetylpiperazin-1-yl butyl —CH₂CH₂CH₂CH₂— 4-acetylpiperazin-1-yl2-methoxyethyl —CH₂CH₂CH₂CH₂— 4-acetylpiperazin-1-yl ethoxymethyl—CH₂CH₂CH₂CH₂— 4-(2-hydroxyethyl)piperazin-1-yl ethyl —CH₂CH₂CH₂CH₂—4-(2-hydroxyethyl)piperazin-1-yl propyl —CH₂CH₂CH₂CH₂—4-(2-hydroxethyl)piperazin-1-yl butyl —CH₂CH₂CH₂CH₂—4-(2-hydroxyethyl)piperazin-1-yl 2-methoxyethyl —CH₂CH₂CH₂CH₂—4-(2-hydroxyethyl)piperazin-1-yl ethoxymethyl —CH₂CH₂CH₂CH₂—3,4-dihydroisoquinolin-2(1H)-yl ethyl —CH₂CH₂CH₂CH₂—3,4-dihydroisoquinolin-2(1H)-yl propyl —CH₂CH₂CH₂CH₂—3,4-dihydroisoquinolin-2(1H)-yl butyl —CH₂CH₂CH₂CH₂—3,4-dihydroisoquinolin-2(1H)-yl 2-methoxyethyl —CH₂CH₂CH₂CH₂—3,4-dihydroisoquinolin-2(1H)-yl ethoxymethyl —CH₂CH₂CH₂CH₂—4-methyl-1,4-diazepan-1-yl ethyl —CH₂CH₂CH₂CH₂—4-methyl-1,4-diazepan-1-yl propyl —CH₂CH₂CH₂CH₂—4-methyl-1,4-diazepan-1-yl butyl —CH₂CH₂CH₂CH₂—4-methyl-1,4-diazepan-1-yl 2-methoxyethyl —CH₂CH₂CH₂CH₂—4-methyl-1,4-diazepan-1-yl ethoxymethyl —CH₂CH₂CH₂CH₂—4-pyrimidin-2-ylpiperazin-1-yl ethyl —CH₂CH₂CH₂CH₂—4-pyrimidin-2-ylpiperazin-1-yl propyl —CH₂CH₂CH₂CH₂—4-pyrimidin-2-ylpiperazin-1-yl butyl —CH₂CH₂CH₂CH₂—4-pyrimidin-2-ylpiperazin-1-yl 2-methoxyethyl —CH₂CH₂CH₂CH₂—4-pyrimidin-2-ylpiperazin-1-yl ethoxymethyl —CH₂CH₂CH₂CH₂CH₂—(methylsulfonyl)amino ethyl —CH₂CH₂CH₂CH₂CH₂— (methylsulfonyl)aminopropyl —CH₂CH₂CH₂CH₂CH₂— (methylsulfonyl)amino butyl —CH₂CH₂CH₂CH₂CH₂—(methylsulfonyl)amino 2-methoxyethyl —CH₂CH₂CH₂CH₂CH₂—(methylsulfonyl)amino ethoxymethyl —CH₂CH₂CH₂CH₂CH₂— pyrrolidin-1-ylethyl —CH₂CH₂CH₂CH₂CH₂— pyrrolidin-1-yl propyl —CH₂CH₂CH₂CH₂CH₂—pyrrolidin-1-yl butyl —CH₂CH₂CH₂CH₂CH₂— pyrrolidin-1-yl 2-methoxyethyl—CH₂CH₂CH₂CH₂CH₂— pyrrolidin-1-yl ethoxymethyl —CH₂CH₂CH₂CH₂CH₂—morpholin-4-yl ethyl —CH₂CH₂CH₂CH₂CH₂— morpholin-4-yl propyl—CH₂CH₂CH₂CH₂CH₂— morpholin-4-yl butyl —CH₂CH₂CH₂CH₂CH₂— morpholin-4-yl2-methoxyethyl —CH₂CH₂CH₂CH₂CH₂— morpholin-4-yl ethoxymethyl—CH₂CH₂CH₂CH₂CH₂— piperidin-1-yl ethyl —CH₂CH₂CH₂CH₂CH₂— piperidin-1-ylpropyl —CH₂CH₂CH₂CH₂CH₂— piperidin-1-yl butyl —CH₂CH₂CH₂CH₂CH₂—piperidin-1-yl 2-methoxyethyl —CH₂CH₂CH₂CH₂CH₂— piperidin-1-ylethoxymethyl —CH₂CH₂CH₂CH₂CH₂— azepan-1-yl ethyl —CH₂CH₂CH₂CH₂CH₂—azepan-1-yl propyl —CH₂CH₂CH₂CH₂CH₂— azepan-1-yl butyl —CH₂CH₂CH₂CH₂CH₂—azepan-1-yl 2-methoxyethyl —CH₂CH₂CH₂CH₂CH₂— azepan-1-yl ethoxymethyl—CH₂CH₂CH₂CH₂CH₂— 4-ethylpiperazin-1-yl ethyl —CH₂CH₂CH₂CH₂CH₂—4-ethylpiperazin-1-yl propyl —CH₂CH₂CH₂CH₂CH₂— 4-ethylpiperazin-1-ylbutyl —CH₂CH₂CH₂CH₂CH₂— 4-ethylpiperazin-1-yl 2-methoxyethyl—CH₂CH₂CH₂CH₂CH₂— 4-ethylpiperazin-1-yl ethoxymethyl —CH₂CH₂CH₂CH₂CH₂—4-acetylpiperazin-1-yl ethyl —CH₂CH₂CH₂CH₂CH₂— 4-acetylpiperazin-1-ylpropyl —CH₂CH₂CH₂CH₂CH₂— 4-acetylpiperazin-1-yl butyl —CH₂CH₂CH₂CH₂CH₂—4-acetylpiperazin-1-yl 2-methoxyethyl —CH₂CH₂CH₂CH₂CH₂—4-acetylpiperazin-1-yl ethoxymethyl —CH₂CH₂CH₂CH₂CH₂—4-(2-hydroxyethyl)piperazin-1-yl ethyl —CH₂CH₂CH₂CH₂CH₂—4-(2-hydroxyethyl)piperazin-1-yl propyl —CH₂CH₂CH₂CH₂CH₂—4-(2-hydroxethyl)piperazin-1-yl butyl —CH₂CH₂CH₂CH₂CH₂—4-(2-hydroxyethyl)piperazin-1-yl 2-methoxyethyl —CH₂CH₂CH₂CH₂CH₂—4-(2-hydroxyethyl)piperazin-1-yl ethoxymethyl —CH₂CH₂CH₂CH₂CH₂—3,4-dihydroisoquinolin-2(1H)-yl ethyl —CH₂CH₂CH₂CH₂CH₂—3,4-dihydroisoquinolin-2(1H)-yl propyl —CH₂CH₂CH₂CH₂CH₂—3,4-dihydroisoquinolin-2(1H)-yl butyl —CH₂CH₂CH₂CH₂CH₂—3,4-dihydroisoquinolin-2(1H)-yl 2-methoxyethyl —CH₂CH₂CH₂CH₂CH₂—3,4-dihydroisoquinolin-2(1H)-yl ethoxymethyl —CH₂CH₂CH₂CH₂CH₂—4-methyl-1,4-diazepan-1-yl ethyl —CH₂CH₂CH₂CH₂CH₂—4-methyl-1,4-diazepan-1-yl propyl —CH₂CH₂CH₂CH₂CH₂—4-methyl-1,4-diazepan-1-yl butyl —CH₂CH₂CH₂CH₂CH₂—4-methyl-1,4-diazepan-1-yl 2-methoxyethyl —CH₂CH₂CH₂CH₂CH₂—4-methyl-1,4-diazepan-1-yl ethoxymethyl —CH₂CH₂CH₂CH₂CH₂—4-pyrimidin-2-ylpiperazin-1-yl ethyl —CH₂CH₂CH₂CH₂CH₂—4-pyrimidin-2-ylpiperazin-1-yl propyl —CH₂CH₂CH₂CH₂CH₂—4-pyrimidin-2-ylpiperazin-1-yl butyl —CH₂CH₂CH₂CH₂CH₂—4-pyrimidin-2-ylpiperazin-1-yl 2-methoxyethyl —CH₂CH₂CH₂CH₂CH₂—4-pyrimidin-2-ylpiperazin-1-yl ethoxymethyl —CH₂CH₂CH₂CH₂CH₂CH₂—(methylsulfonyl)amino ethyl —CH₂CH₂CH₂CH₂CH₂CH₂— (methylsulfonyl)aminopropyl —CH₂CH₂CH₂CH₂CH₂CH₂— (methylsulfonyl)amino butyl—CH₂CH₂CH₂CH₂CH₂CH₂— (methylsulfonyl)amino 2-methoxyethyl—CH₂CH₂CH₂CH₂CH₂CH₂— (methylsulfonyl)amino ethoxymethyl—CH₂CH₂CH₂CH₂CH₂CH₂— pyrrolidin-1-yl ethyl —CH₂CH₂CH₂CH₂CH₂CH₂—pyrrolidin-1-yl propyl —CH₂CH₂CH₂CH₂CH₂CH₂— pyrrolidin-1-yl butyl—CH₂CH₂CH₂CH₂CH₂CH₂— pyrrolidin-1-yl 2-methoxyethyl —CH₂CH₂CH₂CH₂CH₂CH₂—pyrrolidin-1-yl ethoxymethyl —CH₂CH₂CH₂CH₂CH₂CH₂— morpholin-4-yl ethyl—CH₂CH₂CH₂CH₂CH₂CH₂— morpholin-4-yl propyl —CH₂CH₂CH₂CH₂CH₂CH₂—morpholin-4-yl butyl —CH₂CH₂CH₂CH₂CH₂CH₂— morpholin-4-yl 2-methoxyethyl—CH₂CH₂CH₂CH₂CH₂CH₂— morpholin-4-yl ethoxymethyl —CH₂CH₂CH₂CH₂CH₂CH₂—piperidin-1-yl ethyl —CH₂CH₂CH₂CH₂CH₂CH₂— piperidin-1-yl propyl—CH₂CH₂CH₂CH₂CH₂CH₂— piperidin-1-yl butyl —CH₂CH₂CH₂CH₂CH₂CH₂—piperidin-1-yl 2-methoxyethyl —CH₂CH₂CH₂CH₂CH₂CH₂— piperidin-1-ylethoxymethyl —CH₂CH₂CH₂CH₂CH₂CH₂— azepan-1-yl ethyl —CH₂CH₂CH₂CH₂CH₂CH₂—azepan-1-yl propyl —CH₂CH₂CH₂CH₂CH₂CH₂— azepan-l -yl butyl—CH₂CH₂CH₂CH₂CH₂CH₂— azepan-1-yl 2-methoxyethyl —CH₂CH₂CH₂CH₂CH₂CH₂—azepan-1-yl ethoxymethyl —CH₂CH₂CH₂CH₂CH₂CH₂— 4-ethylpiperazin-1-ylethyl —CH₂CH₂CH₂CH₂CH₂CH₂— 4-ethylpiperazin-1-yl propyl—CH₂CH₂CH₂CH₂CH₂CH₂— 4-ethylpiperazin-1-yl butyl —CH₂CH₂CH₂CH₂CH₂CH₂—4-ethylpiperazin-1-yl 2-methoxyethyl —CH₂CH₂CH₂CH₂CH₂CH₂—4-ethylpiperazin-1-yl ethoxymethyl —CH₂CH₂CH₂CH₂CH₂CH₂—4-acetylpiperazin-1-yl ethyl —CH₂CH₂CH₂CH₂CH₂CH₂— 4-acetylpiperazin-1-ylpropyl —CH₂CH₂CH₂CH₂CH₂CH₂— 4-acetylpiperazin-1-yl butyl—CH₂CH₂CH₂CH₂CH₂CH₂— 4-acetylpiperazin-1-yl 2-methoxyethyl—CH₂CH₂CH₂CH₂CH₂CH₂— 4-acetylpiperazin-1-yl ethoxymethyl—CH₂CH₂CH₂CH₂CH₂CH₂— 4-(2-hydroxyethyl)piperazin-1-yl ethyl—CH₂CH₂CH₂CH₂CH₂CH₂— 4-(2-hydroxyethyl)piperazin-1-yl propyl—CH₂CH₂CH₂CH₂CH₂CH₂— 4-(2-hydroxethyl)piperazin-1-yl butyl—CH₂CH₂CH₂CH₂CH₂CH₂— 4-(2-hydroxyethyl)piperazin-1-yl 2-methoxyethyl—CH₂CH₂CH₂CH₂CH₂CH₂— 4-(2-hydroxyethyl)piperazin-1-yl ethoxymethyl—CH₂CH₂CH₂CH₂CH₂CH₂— 3,4-dihydroisoquinolin-2(1H)-yl ethyl—CH₂CH₂CH₂CH₂CH₂CH₂— 3,4-dihydroisoquinolin-2(1H)-yl propyl—CH₂CH₂CH₂CH₂CH₂CH₂— 3,4-dihydroisoquinolin-2(1H)-yl butyl—CH₂CH₂CH₂CH₂CH₂CH₂— 3,4-dihydroisoquinolin-2(1H)-yl 2-methoxyethyl—CH₂CH₂CH₂CH₂CH₂CH₂— 3,4-dihydroisoquinolin-2(1H)-yl ethoxymethyl—CH₂CH₂CH₂CH₂CH₂CH₂— 4-methyl-1,4-diazepan-1-yl ethyl—CH₂CH₂CH₂CH₂CH₂CH₂— 4-methyl-1,4-diazepan-1-yl propyl—CH₂CH₂CH₂CH₂CH₂CH₂— 4-methyl-1,4-diazepan-1-yl butyl—CH₂CH₂CH₂CH₂CH₂CH₂— 4-methyl-1,4-diazepan-1-yl 2-methoxyethyl—CH₂CH₂CH₂CH₂CH₂CH₂— 4-methyl-1,4-diazepan-1-yl ethoxymethyl—CH₂CH₂CH₂CH₂CH₂CH₂— 4-pyrimidin-2-ylpiperazin-1-yl ethyl—CH₂CH₂CH₂CH₂CH₂CH₂— 4-pyrimidin-2-ylpiperazin-1-yl propyl—CH₂CH₂CH₂CH₂CH₂CH₂— 4-pyrimidin-2-ylpiperazin-1-yl butyl—CH₂CH₂CH₂CH₂CH₂CH₂— 4-pyrimidin-2-ylpiperazin-1-yl 2-methoxyethyl—CH₂CH₂CH₂CH₂CH₂CH₂— 4-pyrimidin-2-ylpiperazin-1-yl ethoxymethyl—CH₂CH₂OCH₂CH₂— (methylsulfonyl)amino ethyl —CH₂CH₂OCH₂CH₂—(methylsulfonyl)amino propyl —CH₂CH₂OCH₂CH₂— (methylsulfonyl)amino butyl—CH₂CH₂OCH₂CH₂— (methylsulfonyl)amino 2-methoxyethyl —CH₂CH₂OCH₂CH₂—(methylsulfonyl)amino ethoxymethyl —CH₂CH₂OCH₂CH₂— pyrrolidin-1-yl ethyl—CH₂CH₂OCH₂CH₂— pyrrolidin-1-yl propyl —CH₂CH₂OCH₂CH₂— pyrrolidin-1-ylbutyl —CH₂CH₂OCH₂CH₂— pyrrolidin-1-yl 2-methoxyethyl —CH₂CH₂OCH₂CH₂—pyrrolidin-1-yl ethoxymethyl —CH₂CH₂OCH₂CH₂— morpholin-4-yl ethyl—CH₂CH₂OCH₂CH₂— morpholin-4-yl propyl —CH₂CH₂OCH₂CH₂— morpholin-4-ylbutyl —CH₂CH₂OCH₂CH₂— morpholin-4-yl 2-methoxyethyl —CH₂CH₂OCH₂CH₂—morpholin-4-yl ethoxymethyl —CH₂CH₂OCH₂CH₂— piperidin-1-yl ethyl—CH₂CH₂OCH₂CH₂— piperidin-1-yl propyl —CH₂CH₂OCH₂CH₂— piperidin-1-ylbutyl —CH₂CH₂OCH₂CH₂— piperidin-1-yl 2-methoxyethyl —CH₂CH₂OCH₂CH₂—piperidin-1-yl ethoxymethyl —CH₂CH₂OCH₂CH₂— azepan-1-yl ethyl—CH₂CH₂OCH₂CH₂— azepan-1-yl propyl —CH₂CH₂OCH₂CH₂— azepan-1-yl butyl—CH₂CH₂OCH₂CH₂— azepan-1-yl 2-methoxyethyl —CH₂CH₂OCH₂CH₂— azepan-1-ylethoxymethyl —CH₂CH₂OCH₂CH₂— 4-ethylpiperazin-1-yl ethyl —CH₂CH₂OCH₂CH₂—4-ethylpiperazin-1-yl propyl —CH₂CH₂OCH₂CH₂— 4-ethylpiperazin-1-yl butyl—CH₂CH₂OCH₂CH₂— 4-ethylpiperazin-1-yl 2-methoxyethyl —CH₂CH₂OCH₂CH₂—4-ethylpiperazin-1-yl ethoxymethyl —CH₂CH₂OCH₂CH₂—4-acetylpiperazin-1-yl ethyl —CH₂CH₂OCH₂CH₂— 4-acetylpiperazin-1-ylpropyl —CH₂CH₂OCH₂CH₂— 4-acetylpiperazin-1-yl butyl —CH₂CH₂OCH₂CH₂—4-acetylpiperazin-1-yl 2-methoxyethyl —CH₂CH₂OCH₂CH₂—4-acetylpiperazin-1-yl ethoxymethyl —CH₂CH₂OCH₂CH₂—4-(2-hydroxyethyl)piperazin-1-yl ethyl —CH₂CH₂OCH₂CH₂—4-(2-hydroxyethyl)piperazin-1-yl propyl —CH₂CH₂OCH₂CH₂—4-(2-hydroxethyl)piperazin-1-yl butyl —CH₂CH₂OCH₂CH₂—4-(2-hydroxyethyl)piperazin-1-yl 2-methoxyethyl —CH₂CH₂OCH₂CH₂—4-(2-hydroxyethyl)piperazin-1-yl ethoxymethyl —CH₂CH₂OCH₂CH₂—3,4-dihydroisoquinolin-2(1H)-yl ethyl —CH₂CH₂OCH₂CH₂—3,4-dihydroisoquinolin-2(1H)-yl propyl —CH₂CH₂OCH₂CH₂—3,4-dihydroisoquinolin-2(1H)-yl butyl —CH₂CH₂OCH₂CH₂—3,4-dihydroisoquinolin-2(1H)-yl 2-methoxyethyl —CH₂CH₂OCH₂CH₂—3,4-dihydroisoquinolin-2(1H)-yl ethoxymethyl —CH₂CH₂OCH₂CH₂—4-methyl-1,4-diazepan-1-yl ethyl —CH₂CH₂OCH₂CH₂—4-methyl-1,4-diazepan-1-yl propyl —CH₂CH₂OCH₂CH₂—4-methyl-1,4-diazepan-1-yl butyl —CH₂CH₂OCH₂CH₂—4-methyl-1,4-diazepan-1-yl 2-methoxyethyl —CH₂CH₂OCH₂CH₂—4-methyl-1,4-diazepan-1-yl ethoxymethyl —CH₂CH₂OCH₂CH₂—4-pyrimidin-2-ylpiperazin-1-yl ethyl —CH₂CH₂OCH₂CH₂—4-pyrimidin-2-ylpiperazin-1-yl propyl —CH₂CH₂OCH₂CH₂—4-pyrimidin-2-ylpiperazin-1-yl butyl —CH₂CH₂OCH₂CH₂—4-pyrimidin-2-ylpiperazin-1-yl 2-methoxyethyl —CH₂CH₂OCH₂CH₂—4-pyrimidin-2-ylpiperazin-1-yl ethoxymethyl

Certain exemplary compounds, including some of those described above inthe Examples, have the following Formula (IIe) and the following Z,R_(3e), and R₂, substituents, wherein each line of the table is matchedwith Formula IIe to represent a specific embodiment of the invention.

IIe

Z R_(3e) R₂ —CH₂CH₂— (phenylaminocarbonyl)amino ethyl —CH₂CH₂—(phenylaminocarbonyl)amino propyl —CH₂CH₂— (phenylaminocarbonyl)aminobutyl —CH₂CH₂— (phenylaminocarbonyl)amino 2-methoxyethyl —CH₂CH₂—(phenylaminocarbonyl)amino ethoxymethyl —CH₂CH₂—(phenylaminocarbonothioyl)amino ethyl —CH₂CH₂—(phenylaminocarbonothioyl)amino propyl —CH₂CH₂—(phenylaminocarbonothioyl)amino butyl —CH₂CH₂—(phenylaminocarbonothioyl)amino 2-methoxyethyl —CH₂CH₂—(phenylaminocarbonothioyl)amino ethoxymethyl —CH₂CH₂—{[(3-methoxyphenyl)amino]- ethyl carbonyl}amino —CH₂CH₂—{[(3-methoxyphenyl)amino]- propyl carbonyl}amino —CH₂CH₂—{[(3-methoxyphenyl)amino]- butyl carbonyl}amino —CH₂CH₂—{[(3-methoxyphenyl)amino]- 2-methoxyethyl carbonyl}amino —CH₂CH₂—{[(3-methoxyphenyl)amino]- ethoxymethyl carbonyl}amino —CH₂CH₂—methyl(1-methylpiperdin-4- ethyl yl)amino —CH₂CH₂—methyl(1-methylpiperdin-4- propyl yl)amino —CH₂CH₂—methyl(1-methylpiperdin-4- butyl yl)amino —CH₂CH₂—methyl(1-methylpiperdin-4- 2-methoxyethyl yl)amino —CH₂CH₂—methyl(1-methylpiperdin-4- ethoxymethyl yl)amino —CH₂CH₂—4-pyrrolidin-1-ylpiperidin-1-yl ethyl —CH₂CH₂—4-pyrrolidin-1-ylpiperidin-1-yl propyl —CH₂CH₂—4-pyrrolidin-1-ylpiperidin-1-yl butyl —CH₂CH₂—4-pyrrolidin-1-ylpiperidin-1-yl 2-methoxyethyl —CH₂CH₂—4-pyrrolidin-1-ylpiperidin-1-yl ethoxymethyl —CH₂CH₂—1,4′-bipiperidin-1′-yl ethyl —CH₂CH₂— 1,4′-bipiperidin-1′-yl propyl—CH₂CH₂— 1,4′-bipiperidin-1′-yl butyl —CH₂CH₂— 1,4′-bipiperidin-1′-yl2-methoxyethyl —CH₂CH₂— 1,4′-bipiperidin-1′-yl ethoxymethyl —CH₂CH₂CH₂—(phenylaminocarbonyl)amino ethyl —CH₂CH₂CH₂— (phenylaminocarbonyl)aminopropyl —CH₂CH₂CH₂— (phenylaminocarbonyl)amino butyl —CH₂CH₂CH₂—(phenylaminocarbonyl)amino 2-methoxyethyl —CH₂CH₂CH₂—(phenylaminocarbonyl)amino ethoxymethyl —CH₂CH₂CH₂—(phenylaminocarbonothioyl)amino ethyl —CH₂CH₂CH₂—(phenylaminocarbonothioyl)amino propyl —CH₂CH₂CH₂—(phenylaminocarbonothioyl)amino butyl —CH₂CH₂CH₂—(phenylaminocarbonothioyl)amino 2-methoxyethyl —CH₂CH₂CH₂—(phenylaminocarbonothioyl)amino ethoxymethyl —CH₂CH₂CH₂—{[(3-methoxyphenyl)amino]- ethyl carbonyl}amino —CH₂CH₂CH₂—{[(3-methoxyphenyl)amino]- propyl carbonyl}amino —CH₂CH₂CH₂—{[(3-methoxyphenyl)amino]- butyl carbonyl}amino —CH₂CH₂CH₂—{[(3-methoxyphenyl)amino]- 2-methoxyethyl carbonyl}amino —CH₂CH₂CH₂—{[(3-methoxyphenyl)amino]- ethoxymethyl carbonyl}amino —CH₂CH₂CH₂—methyl(1-methylpiperdin-4- ethyl yl)amino —CH₂CH₂CH₂—methyl(1-methylpiperdin-4- propyl yl)amino —CH₂CH₂CH₂—methyl(1-methylpiperdin-4- butyl yl)amino —CH₂CH₂CH₂—methyl(1-methylpiperdin-4- 2-methoxyethyl yl)amino —CH₂CH₂CH₂—methyl(1-methylpiperdin-4- ethoxymethyl yl)amino —CH₂CH₂CH₂—4-pyrrolidin-1-ylpiperidin-1-yl ethyl —CH₂CH₂CH₂—4-pyrrolidin-1-ylpiperidin-1-yl propyl —CH₂CH₂CH₂—4-pyrrolidin-1-ylpiperidin-1-yl butyl —CH₂CH₂CH₂—4-pyrrolidin-1-ylpiperidin-1-yl 2-methoxyethyl —CH₂CH₂CH₂—4-pyrrolidin-1-ylpiperidin-1-yl ethoxymethyl —CH₂CH₂CH₂—1,4′-bipiperidin-1′-yl ethyl —CH₂CH₂CH₂— 1,4′-bipiperidin-1′-yl propyl—CH₂CH₂CH₂— 1,4′-bipiperidin-1′-yl butyl —CH₂CH₂CH₂—1,4′-bipiperidin-1′-yl 2-methoxyethyl —CH₂CH₂CH₂— 1,4′-bipiperidin-1′-ylethoxymethyl —CH₂CH₂CH₂CH₂— (phenylaminocarbonyl)amino ethyl—CH₂CH₂CH₂CH₂— (phenylaminocarbonyl)amino propyl —CH₂CH₂CH₂CH₂—(phenylaminocarbonyl)amino butyl —CH₂CH₂CH₂CH₂—(phenylaminocarbonyl)amino 2-methoxyethyl —CH₂CH₂CH₂CH₂—(phenylaminocarbonyl)amino ethoxymethyl —CH₂CH₂CH₂CH₂—(phenylaminocarbonothioyl)amino ethyl —CH₂CH₂CH₂CH₂—(phenylaminocarbonothioyl)amino propyl —CH₂CH₂CH₂CH₂—(phenylaminocarbonothioyl)amino butyl —CH₂CH₂CH₂CH₂—(phenylaminocarbonothioyl)amino 2-methoxyethyl —CH₂CH₂CH₂CH₂—(phenylaminocarbonothioyl)amino ethoxymethyl —CH₂CH₂CH₂CH₂—{[(3-methoxyphenyl)amino]- ethyl carbonyl}amino —CH₂CH₂CH₂CH₂—{[(3-methoxyphenyl)amino]- propyl carbonyl}amino —CH₂CH₂CH₂CH₂—{[(3-methoxyphenyl)amino]- butyl carbonyl}amino —CH₂CH₂CH₂CH₂—{[(3-methoxyphenyl)amino]- 2-methoxyethyl carbonyl}amino —CH₂CH₂CH₂CH₂—{[(3-methoxyphenyl)amino]- ethoxymethyl carbonyl}amino —CH₂CH₂CH₂CH₂—methyl(1-methylpiperdin-4- ethyl yl)amino —CH₂CH₂CH₂CH₂—methyl(1-methylpiperdin-4- propyl yl)amino —CH₂CH₂CH₂CH₂—methyl(1-methylpiperdin-4- butyl yl)amino —CH₂CH₂CH₂CH₂—methyl(1-methylpiperdin-4- 2-methoxyethyl yl)amino —CH₂CH₂CH₂CH₂—methyl(1-methylpiperdin-4- ethoxymethyl yl)amino —CH₂CH₂CH₂CH₂—4-pyrrolidin-1-ylpiperidin-1-yl ethyl —CH₂CH₂CH₂CH₂—4-pyrrolidin-1-ylpiperidin-1-yl propyl —CH₂CH₂CH₂CH₂—4-pyrrolidin-1-ylpiperidin-1-yl butyl —CH₂CH₂CH₂CH₂—4-pyrrolidin-1-ylpiperidin-1-yl 2-methoxyethyl —CH₂CH₂CH₂CH₂—4-pyrrolidin-1-ylpiperidin-1-yl ethoxymethyl —CH₂CH₂CH₂CH₂—1,4′-bipiperidin-1′-yl ethyl —CH₂CH₂CH₂CH₂— 1,4′-bipiperidin-1′-ylpropyl —CH₂CH₂CH₂CH₂— 1,4′-bipiperidin-1′-yl butyl —CH₂CH₂CH₂CH₂—1,4′-bipiperidin-1′-yl 2-methoxyethyl —CH₂CH₂CH₂CH₂—1,4′-bipiperidin-1′-yl ethoxymethyl —CH₂CH₂CH₂CH₂CH₂—(phenylaminocarbonyl)amino ethyl —CH₂CH₂CH₂CH₂CH₂—(phenylaminocarbonyl)amino propyl —CH₂CH₂CH₂CH₂CH₂—(phenylaminocarbonyl)amino butyl —CH₂CH₂CH₂CH₂CH₂—(phenylaminocarbonyl)amino 2-methoxyethyl —CH₂CH₂CH₂CH₂CH₂—(phenylaminocarbonyl)amino ethoxymethyl —CH₂CH₂CH₂CH₂CH₂—(phenylaminocarbonothioyl)amino ethyl —CH₂CH₂CH₂CH₂CH₂—(phenylaminocarbonothioyl)amino propyl —CH₂CH₂CH₂CH₂CH₂—(phenylaminocarbonothioyl)amino butyl —CH₂CH₂CH₂CH₂CH₂—(phenylaminocarbonothioyl)amino 2-methoxyethyl —CH₂CH₂CH₂CH₂CH₂—(phenylaminocarbonothioyl)amino ethoxymethyl —CH₂CH₂CH₂CH₂CH₂—{[(3-methoxyphenyl)amino]- ethyl carbonyl}amino —CH₂CH₂CH₂CH₂CH₂—{[(3-methoxyphenyl)amino]- propyl carbonyl}amino —CH₂CH₂CH₂CH₂CH₂—{[(3-methoxyphenyl)amino]- butyl carbonyl}amino —CH₂CH₂CH₂CH₂CH₂—{[(3-methoxyphenyl)amino]- 2-methoxyethyl carbonyl}amino—CH₂CH₂CH₂CH₂CH₂— {[(3-methoxyphenyl)amino]- ethoxymethyl carbonyl}amino—CH₂CH₂CH₂CH₂CH₂— methyl(1-methylpiperdin-4- ethyl yl)amino—CH₂CH₂CH₂CH₂CH₂— methyl(1-methylpiperdin-4- propyl yl)amino—CH₂CH₂CH₂CH₂CH₂— methyl(1-methylpiperdin-4- butyl yl)amino—CH₂CH₂CH₂CH₂CH₂— methyl(1-methylpiperdin-4- 2-methoxyethyl yl)amino—CH₂CH₂CH₂CH₂CH₂— methyl(1-methylpiperdin-4- ethoxymethyl yl)amino—CH₂CH₂CH₂CH₂CH₂— 4-pyrrolidin-1-ylpiperidin-1-yl ethyl—CH₂CH₂CH₂CH₂CH₂— 4-pyrrolidin-1-ylpiperidin-1-yl propyl—CH₂CH₂CH₂CH₂CH₂— 4-pyrrolidin-1-ylpiperidin-1-yl butyl—CH₂CH₂CH₂CH₂CH₂— 4-pyrrolidin-1-ylpiperidin-1-yl 2-methoxyethyl—CH₂CH₂CH₂CH₂CH₂— 4-pyrrolidin-1-ylpiperidin-1-yl ethoxymethyl—CH₂CH₂CH₂CH₂CH₂— 1,4′-bipiperidin-1′-yl ethyl —CH₂CH₂CH₂CH₂CH₂—1,4′-bipiperidin-1′-yl propyl —CH₂CH₂CH₂CH₂CH₂— 1,4′-bipiperidin-1′-ylbutyl —CH₂CH₂CH₂CH₂CH₂— 1,4′-bipiperidin-1′-yl 2-methoxyethyl—CH₂CH₂CH₂CH₂CH₂— 1,4′-bipiperidin-1′-yl ethoxymethyl—CH₂CH₂CH₂CH₂CH₂CH₂— (phenylaminocarbonyl)amino ethyl—CH₂CH₂CH₂CH₂CH₂CH₂— (phenylaminocarbonyl)amino propyl—CH₂CH₂CH₂CH₂CH₂CH₂— (phenylaminocarbonyl)amino butyl—CH₂CH₂CH₂CH₂CH₂CH₂— (phenylaminocarbonyl)amino 2-methoxyethyl—CH₂CH₂CH₂CH₂CH₂CH₂— (phenylaminocarbonyl)amino ethoxymethyl—CH₂CH₂CH₂CH₂CH₂CH₂— (phenylaminocarbonothioyl)amino ethyl—CH₂CH₂CH₂CH₂CH₂CH₂— (phenylaminocarbonothioyl)amino propyl—CH₂CH₂CH₂CH₂CH₂CH₂— (phenylaminocarbonothioyl)amino butyl—CH₂CH₂CH₂CH₂CH₂CH₂— (phenylaminocarbonothioyl)amino 2-methoxyethyl—CH₂CH₂CH₂CH₂CH₂CH₂— (phenylaminocarbonothioyl)amino ethoxymethyl—CH₂CH₂CH₂CH₂CH₂CH₂— {[(3-methoxyphenyl)amino]- ethyl carbonyl}amino—CH₂CH₂CH₂CH₂CH₂CH₂— {[(3-methoxyphenyl)amino]- propyl carbonyl}amino—CH₂CH₂CH₂CH₂CH₂CH₂— {[(3-methoxyphenyl)amino]- butyl carbonyl}amino—CH₂CH₂CH₂CH₂CH₂CH₂— {[(3-methoxyphenyl)amino]- 2-methoxyethylcarbonyl}amino —CH₂CH₂CH₂CH₂CH₂CH₂— {[(3-methoxyphenyl)amino]-ethoxymethyl carbonyl}amino —CH₂CH₂CH₂CH₂CH₂CH₂—methyl(1-methylpiperdin-4- ethyl yl)amino —CH₂CH₂CH₂CH₂CH₂CH₂—methyl(1-methylpiperdin-4- propyl yl)amino —CH₂CH₂CH₂CH₂CH₂CH₂—methyl(1-methylpiperdin-4- butyl yl)amino —CH₂CH₂CH₂CH₂CH₂CH₂—methyl(1-methylpiperdin-4- 2-methoxyethyl yl)amino —CH₂CH₂CH₂CH₂CH₂CH₂—methyl(1-methylpiperdin-4- ethoxymethyl yl)amino —CH₂CH₂CH₂CH₂CH₂CH₂—4-pyrrolidin-1-ylpiperidin-1-yl ethyl —CH₂CH₂CH₂CH₂CH₂CH₂—4-pyrrolidin-1-ylpiperidin-1-yl propyl —CH₂CH₂CH₂CH₂CH₂CH₂—4-pyrrolidin-1-ylpiperidin-1-yl butyl —CH₂CH₂CH₂CH₂CH₂CH₂—4-pyrrolidin-1-ylpiperidin-1-yl 2-methoxyethyl —CH₂CH₂CH₂CH₂CH₂CH₂—4-pyrrolidin-1-ylpiperidin-1-yl ethoxymethyl —CH₂CH₂CH₂CH₂CH₂CH₂—1,4′-bipiperidin-1′-yl ethyl —CH₂CH₂CH₂CH₂CH₂CH₂— 1,4′-bipiperidin-1′-ylpropyl —CH₂CH₂CH₂CH₂CH₂CH₂— 1,4′-bipiperidin-1′-yl butyl—CH₂CH₂CH₂CH₂CH₂CH₂— 1,4′-bipiperidin-1′-yl 2-methoxyethyl—CH₂CH₂CH₂CH₂CH₂CH₂— 1,4′-bipiperidin-1′-yl ethoxymethyl —CH₂CH₂OCH₂CH₂—(phenylaminocarbonyl)amino ethyl —CH₂CH₂OCH₂CH₂—(phenylaminocarbonyl)amino propyl —CH₂CH₂OCH₂CH₂—(phenylaminocarbonyl)amino butyl —CH₂CH₂OCH₂CH₂—(phenylaminocarbonyl)amino 2-methoxyethyl —CH₂CH₂OCH₂CH₂—(phenylaminocarbonyl)amino ethoxymethyl —CH₂CH₂OCH₂CH₂—(phenylaminocarbonothioyl)amino ethyl —CH₂CH₂OCH₂CH₂—(phenylaminocarbonothioyl)amino propyl —CH₂CH₂OCH₂CH₂—(phenylaminocarbonothioyl)amino butyl —CH₂CH₂OCH₂CH₂—(phenylaminocarbonothioyl)amino 2-methoxyethyl —CH₂CH₂OCH₂CH₂—(phenylaminocarbonothioyl)amino ethoxymethyl —CH₂CH₂OCH₂CH₂—{[(3-methoxyphenyl)amino]- ethyl carbonyl}amino —CH₂CH₂OCH₂CH₂—{[(3-methoxyphenyl)amino]- propyl carbonyl}amino —CH₂CH₂OCH₂CH₂—{[(3-methoxyphenyl)amino]- butyl carbonyl}amino —CH₂CH₂OCH₂CH₂—{[(3-methoxyphenyl)amino]- 2-methoxyethyl carbonyl}amino —CH₂CH₂OCH₂CH₂—{[(3-methoxyphenyl)amino]- ethoxymethyl carbonyl}amino —CH₂CH₂OCH₂CH₂—methyl(1-methylpiperdin-4- ethyl yl)amino —CH₂CH₂OCH₂CH₂—methyl(1-methylpiperdin-4- propyl yl)amino —CH₂CH₂OCH₂CH₂—methyl(1-methylpiperdin-4- butyl yl)amino —CH₂CH₂OCH₂CH₂—methyl(1-methylpiperdin-4- 2-methoxyethyl yl)amino —CH₂CH₂OCH₂CH₂—methyl(1-methylpiperdin-4- ethoxymethyl yl)amino —CH₂CH₂OCH₂CH₂—4-pyrrolidin-1-ylpiperidin-1-yl ethyl —CH₂CH₂OCH₂CH₂—4-pyrrolidin-1-ylpiperidin-1-yl propyl —CH₂CH₂OCH₂CH₂—4-pyrrolidin-1-ylpiperidin-1-yl butyl —CH₂CH₂OCH₂CH₂—4-pyrrolidin-1-ylpiperidin-1-yl 2-methoxyethyl —CH₂CH₂OCH₂CH₂—4-pyrrolidin-1-ylpiperidin-1-yl ethoxymethyl —CH₂CH₂OCH₂CH₂—1,4′-bipiperidin-1′-yl ethyl —CH₂CH₂OCH₂CH₂— 1,4′-bipiperidin-1′-ylpropyl —CH₂CH₂OCH₂CH₂— 1,4′-bipiperidin-1′-yl butyl —CH₂CH₂OCH₂CH₂—1,4′-bipiperidin-1′-yl 2-methoxyethyl —CH₂CH₂OCH₂CH₂—1,4′-bipiperidin-1′-yl ethoxymethyl

Compounds of the invention have been found to modulate cytokinebiosynthesis by inducing the production of interferon α and/or tumornecrosis factor a in human cells when tested using one of the methodsdescribed below.

Cytokine Induction in Human Cells

An in vitro human blood cell system is used to assess cytokineinduction. Activity is based on the measurement of interferon (α) andtumor necrosis factor (α) (IFN-α and TNF-α, respectively) secreted intoculture media as described by Testerman et. al. in “Cytokine Inductionby the Immunomodulators Imiquimod and S-27609”, Journal of LeukocyteBiology, 58, 365-372 (September, 1995).

Blood Cell Preparation for Culture

Whole blood from healthy human donors is collected by venipuncture intovacutainer tubes or syringes containing EDTA. Peripheral bloodmononuclear cells (PBMC) are separated from whole blood by densitygradient centrifugation using HISTOPAQUE-1077 (Sigma, St. Louis, Mo.) orFicoll-Paque Plus (Amersham Biosciences Piscataway, N.J.). Blood isdiluted 1:1 with Dulbecco's Phosphate Buffered Saline (DPBS) or Hank'sBalanced Salts Solution (HBSS). Alternately, whole blood is placed inAccuspin (Sigma) or LeucoSep (Greiner Bio-One, Inc., Longwood, Fla.)centrifuge frit tubes containing density gradient medium. The PBMC layeris collected and washed twice with DPBS or HBSS and re-suspended at4×10⁶ cells/mL in RPMI complete. The PBMC suspension is added to 96 wellflat bottom sterile tissue culture plates containing an equal volume ofRPMI complete media containing test compound.

Compound Preparation

The compounds are solubilized in dimethyl sulfoxide (DMSO). The DMSOconcentration should not exceed a final concentration of 1% for additionto the culture wells. The compounds are generally tested atconcentrations ranging from 30-0.014 μM. Controls include cell sampleswith media only, cell samples with DMSO only (no compound), and cellsamples with reference compound.

Incubation

The solution of test compound is added at 60 μM to the first wellcontaining RPMI complete and serial 3 fold dilutions are made in thewells. The PBMC suspension is then added to the wells in an equalvolume, bringing the test compound concentrations to the desired range(usually 30-0.014 μM). The final concentration of PBMC suspension is2×10⁶ cells/mL. The plates are covered with sterile plastic lids, mixedgently and then incubated for 18 to 24 hours at 37° C. in a 5% carbondioxide atmosphere.

Separation

Following incubation the plates are centrifuged for 10 minutes at 1000rpm (approximately 200×g) at 4° C. The cell-free culture supernatant isremoved and transferred to sterile polypropylene tubes. Samples aremaintained at −30 to −70° C. until analysis. The samples are analyzedfor IFN-α by ELISA and for TNF-α by IGEN/BioVeris Assay.

Interferon (α) and Tumor Necrosis Factor (α) Analysis

IFN-α concentration is determined with a human multi-subtypecolorimetric sandwich ELISA (Catalog Number 41105) from PBL BiomedicalLaboratories, Piscataway, N.J. Results are expressed in pg/mL.

The TNF-α concentration is determined by ORIGEN M-Series Immunoassay andread on an IGEN M-8 analyzer from BioVeris Corporation, formerly knownas IGEN

International, Gaithersburg, Md. The immunoassay uses a human TNF-αcapture and detection antibody pair (Catalog Numbers AHC3419 andAHC3712) from Biosource International, Camarillo, Calif. Results areexpressed in pg/mL.

Assay Data and Analysis

In total, the data output of the assay consists of concentration valuesof TNF-α and IFN-α (y-axis) as a function of compound concentration(x-axis).

Analysis of the data has two steps. First, the greater of the mean DMSO(DMSO control wells) or the experimental background (usually 20 pg/mLfor IFN-α and 40 pg/mL for TNF-α) is subtracted from each reading. Ifany negative values result from background subtraction, the reading isreported as “*”, and is noted as not reliably detectable. In subsequentcalculations and statistics, “*”, is treated as a zero. Second, allbackground subtracted values are multiplied by a single adjustment ratioto decrease experiment to experiment variability. The adjustment ratiois the area of the reference compound in the new experiment divided bythe expected area of the reference compound based on the past 61experiments (unadjusted readings). This results in the scaling of thereading (y-axis) for the new data without changing the shape of thedose-response curve. The reference compound used is2-[4-amino-2-ethoxymethyl-6,7,8,9-tetrahydro-α,α-dimethyl-1H-imidazo[4,5-c]quinolin-1-yl]ethanolhydrate (U.S. Pat. No. 5,352,784; Example 91) and the expected area isthe sum of the median dose values from the past 61 experiments.

The minimum effective concentration is calculated based on thebackground-subtracted, reference-adjusted results for a given experimentand compound. The minimum effective concentration (μmolar) is the lowestof the tested compound concentrations that induces a response over afixed cytokine concentration for the tested cytokine (usually 20 pg/mLfor IFN-α and 40 pg/mL for TNF-α). The maximal response is the maximalamount of cytokine (pg/ml) produced in the dose-response.

Cytokine Induction in Human Cells High Throughput Screen

The CYTOKINE INDUCTION IN HUMAN CELLS test method described above wasmodified as follows for high throughput screening.

Blood Cell Preparation for Culture

Whole blood from healthy human donors is collected by venipuncture intovacutainer tubes or syringes containing EDTA. Peripheral bloodmononuclear cells (PBMC) are separated from whole blood by densitygradient centrifugation using HISTOPAQUE-1077 (Sigma, St. Louis, Mo.) orFicoll-Paque Plus (Amersham Biosciences Piscataway, N.J.). Whole bloodis placed in Accuspin (Sigma) or LeucoSep (Greiner Bio-One, Inc.,Longwood, Fla.) centrifuge frit tubes containing density gradientmedium. The PBMC layer is collected and washed twice with DPBS or HBSSand re-suspended at 4×10⁶ cells/mL in RPMI complete (2-fold the finalcell density). The PBMC suspension is added to 96-well flat bottomsterile tissue culture plates.

Compound Preparation

The compounds are solubilized in dimethyl sulfoxide (DMSO). Thecompounds are generally tested at concentrations ranging from 30-0.014μM. Controls include cell samples with media only, cell samples withDMSO only (no compound), and cell samples with a reference compound2-[4-amino-2-ethoxymethyl-6,7,8,9-tetrahydro-α,α-dimethyl-1H-imidazo[4,5-c]quinolin-1-yl]ethanolhydrate (U.S. Pat. No. 5,352,784; Example 91) on each plate. Thesolution of test compound is added at 7.5 mM to the first well of adosing plate and serial 3 fold dilutions are made for the 7 subsequentconcentrations in DMSO. RPMI Complete media is then added to the testcompound dilutions in order to reach a final compound concentration of2-fold higher (60-0.028 μM) than the final tested concentration range.

Incubation

Compound solution is then added to the wells containing the PBMCsuspension bringing the test compound concentrations to the desiredrange (usually 30-0.014 μM) and the DMSO concentration to 0.4%. Thefinal concentration of PBMC suspension is 2×10⁶ cells/mL. The plates arecovered with sterile plastic lids, mixed gently and then incubated for18 to 24 hours at 37° C. in a 5% carbon dioxide atmosphere.

Separation

Following incubation the plates are centrifuged for 10 minutes at 1000rpm (approximately 200 g) at 4° C. 4-plex Human Panel MSD MULTI-SPOT96-well plates are pre-coated with the appropriate capture antibodies byMesoScale Discovery, Inc. (MSD, Gaithersburg, Md.). The cell-freeculture supernatants are removed and transferred to the MSD plates.Fresh samples are typically tested, although they may be maintained at−30 to −70° C. until analysis.

Interferon-α and Tumor Necrosis Factor-α Analysis

MSD MULTI-SPOT plates contain within each well capture antibodies forhuman TNF-α and human IFN-α that have been pre-coated on specific spots.Each well contains four spots: one human TNF-α capture antibody (MSD)spot, one human IFN-α capture antibody (PBL Biomedical Laboratories,Piscataway, N.J.) spot, and two inactive bovine serum albumin spots. Thehuman TNF-α capture and detection antibody pair is from MesoScaleDiscovery. The human IFN-α multi-subtype antibody (PBL BiomedicalLaboratories) captures all IFN-α subtypes except IFN-α F (IFNα21).Standards consist of recombinant human TNF-α (R&D Systems, Minneapolis,Minn.) and IFN-α (PBL Biomedical Laboratories). Samples and separatestandards are added at the time of analysis to each MSD plate. Two humanIFN-α detection antibodies (Cat. Nos. 21112 & 21100, PBL) are used in atwo to one ratio (weight:weight) to each other to determine the IFN-αconcentrations. The cytokine-specific detection antibodies are labeledwith the SULFO-TAG reagent (MSD). After adding the SULFO-TAG labeleddetection antibodies to the wells, each well's electrochemoluminescentlevels are read using MSD's SECTOR HTS READER. Results are expressed inpg/mL upon calculation with known cytokine standards.

Assay Data and Analysis

In total, the data output of the assay consists of concentration valuesof TNF-α or IFN-α (y-axis) as a function of compound concentration(x-axis).

A plate-wise scaling is performed within a given experiment aimed atreducing plate-to-plate variability associated within the sameexperiment. First, the greater of the median DMSO (DMSO control wells)or the experimental background (usually 20 pg/mL for IFN-α and 40 pg/mLfor TNF-α) is subtracted from each reading. Negative values that mayresult from background subtraction are set to zero. Each plate within agiven experiment has a reference compound that serves as a control. Thiscontrol is used to calculate a median expected area under the curveacross all plates in the assay. A plate-wise scaling factor iscalculated for each plate as a ratio of the area of the referencecompound on the particular plate to the median expected area for theentire experiment. The data from each plate are then multiplied by theplate-wise scaling factor for all plates. Only data from plates bearinga scaling factor of between 0.5 and 2.0 (for both cytokines IFN-α,TNF-α) are reported. Data from plates with scaling factors outside theabove mentioned interval are retested until they bear scaling factorsinside the above mentioned interval. The above method produces a scalingof the y-values without altering the shape of the curve. The referencecompound used is2-[4-amino-2-ethoxymethyl-6,7,8,9-tetrahydro-α,α-dimethyl-1H-imidazo[4,5-c]quinolin-1-yl]ethanolhydrate (U.S. Pat. No. 5,352,784; Example 91). The median expected areais the median area across all plates that are part of a givenexperiment.

A second scaling may also be performed to reduce inter-experimentvariability (across multiple experiments). All background-subtractedvalues are multiplied by a single adjustment ratio to decreaseexperiment-to-experiment variability. The adjustment ratio is the areaof the reference compound in the new experiment divided by the expectedarea of the reference compound based on an average of previousexperiments (unadjusted readings). This results in the scaling of thereading (y-axis) for the new data without changing the shape of thedose-response curve. The reference compound used is2-[4-amino-2-ethoxymethyl-6,7,8,9-tetrahydro-α,α-dimethyl-1H-imidazo[4,5-c]quinolin-1-yl]ethanolhydrate (U.S. Pat. No. 5,352,784; Example 91) and the expected area isthe sum of the median dose values from an average of previousexperiments.

The minimum effective concentration is calculated based on thebackground-subtracted, reference-adjusted results for a given experimentand compound. The minimum effective concentration (μmolar) is the lowestof the tested compound concentrations that induces a response over afixed cytokine concentration for the tested cytokine (usually 20 pg/mLfor IFN-α and 40 pg/mL for TNF-α). The maximal response is the maximalamount of cytokine (pg/ml) produced in the dose-response.

The complete disclosures of the patents, patent documents, andpublications cited herein are incorporated by reference in theirentirety as if each were individually incorporated. Variousmodifications and alterations to this invention will become apparent tothose skilled in the art without departing from the scope and spirit ofthis invention. It should be understood that this invention is notintended to be unduly limited by the illustrative embodiments andexamples set forth herein and that such examples and embodiments arepresented by way of example only with the scope of the inventionintended to be limited only by the claims set forth herein as follows.

1. A compound of Formula I:

wherein: R_(A) and R_(B) taken together form a fused benzene ring orfused pyridine ring wherein the benzene ring or pyridine ring issubstituted by one —O—R₃ group, or substituted by one —O—R₃ group andone R group; R₃ is selected from the group consisting of: -Z-Y—R₄,-Z-Y—X—Y—R₄, -Z-Y—X—Y—X—Y—R₄, -Z-R₅, -Z-Het, -Z-Het′-R₄, and-Z-Het′-Y—R₄; R is selected from the group consisting of alkyl, alkoxy,hydroxy, halogen, and trifluoromethyl; R″ is hydrogen or anon-interfering substituent; Z is selected from the group consisting ofalkylene, alkenylene, and alkynylene, wherein alkylene, alkenylene, andalkynylene can be optionally interrupted with one or more —O— groups; Yis selected from the group consisting of: —S(O)₀₋₂—, —S(O)₂—N(R₈)—,—C(R₆)—, —C(R₆)—O—, —O—C(R₆)—, —O—C(O)—O—, —N(R₈)-Q-, —C(R₆)—N(R₈)—,—O—C(R₆)—N(R₈)—, —C(R₆)—N(OR₉)—, —O—N(R₈)-Q-, —O—N═C(R₄)—, —C(═N—O—R₈)—,—CH(—N(—O—R₈)-Q-R₄)—,

Het is heterocyclyl which can be unsubstituted or substituted by one ormore substituents independently selected from the group consisting ofalkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy,hydroxyalkyl, cyano, hydroxyalkyleneoxyalkylenyl, amino, alkylamino,dialkylamino, and oxo; Het′ is heterocyclylene which can beunsubstituted or substituted by one or more substituents independentlyselected from the group consisting of alkyl, alkoxy, haloalkyl,haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, amino,alkylamino, dialkylamino, and oxo; X is selected from the groupconsisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene,and heterocyclylene wherein the alkylene, alkenylene, and alkynylenegroups can be optionally interrupted or terminated with arylene,heteroarylene, or heterocyclylene, and optionally interrupted by one ormore —O— groups; R₄ is selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl,alkylarylenyl, heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo; R₅ is selected from the group consisting of:

R₆ is selected from the group consisting of ═O and ═S; R₇ is C₂₋₇alkylene; R₈ is selected from the group consisting of hydrogen, alkyl,hydroxyalkylenyl, alkoxyalkylenyl, arylalkylenyl, andheteroarylalkylenyl; R₉ is selected from the group consisting ofhydrogen and alkyl; R₁₀ is C₃₋₈ alkylene; A is selected from the groupconsisting of —O—, —CH₂—, —C(O)—, —S(O)₀₋₂—, and —N(R₄)—; A′ is selectedfrom the group consisting of —O—, —S(O)₀₋₂—, —N(-Q-R₄)—, and —CH₂—; Q isselected from the group consisting of a bond, —C(R₆)—, —C(R₆)—C(R₆)—,—S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, and —C(R₆)—N(OR₉)—;V is selected from the group consisting of-C(R₆)—, —O—C(R₆)—,—N(R₈)—C(R₆)—, and —S(O)₂—; W is selected from the group consisting of abond, —C(O)—, and —S(O)₂—; and a and b are independently integers from 1to 6 with the proviso that a+b is ≦7; with the proviso that Z can alsobe a bond when: R₃ is -Z-Het, -Z-Het′-R₄, or -Z-Het′-Y—R₄, and Z isattached to an atom other than N in Het or Het′; or R₃ is -Z-Y—R₄,-Z-Y—X—Y—R₄, or -Z-Y—X—Y—X—Y—R₄, and the Y group bonded to Z is —S(O)₂—,—S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—, —C(R₆)—N(R₈)—,

wherein V is —C(R₆)— or

R₃ is -Z-R₅, and R₅ is

wherein V is —C(R₆)— or —S(O)₂—, or

and with the further proviso that Y can also be —O— when: Y is bonded toR₄, and R₄ is selected from the group consisting of hydrogen, aryl, andheteroaryl, wherein aryl and heteroaryl can be unsubstituted orsubstituted by one or more substituents; or Y is bonded to Z and X, andX is arylene or heteroarylene; or a pharmaceutically acceptable saltthereof.
 2. The compound or salt of claim 1 wherein R″ is R₂; wherein R₂is selected from the group consisting of —R₄, —X—R₄, —X—Y′—R₄, and—X—R₅′; wherein Y′ is selected from the group consisting of: —O—,—S(O)₀₋₂—, —S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—, —O—C(R₆)—, —O—C(O)—O—,—N(R₈)-Q-, —C(R₆)—N(R₈)—, —O—C(R₆)—N(R₈)—, —C(R₆)—N(OR₉)—,

R₅′ is selected from the group consisting of:


3. A compound of Formula VII:

wherein: R_(A) and R_(B) taken together form a fused benzene ring orfused pyridine ring wherein the benzene ring or pyridine ring issubstituted by one —O—R₃ group, or substituted by one —O—R₃ group andone R group; R₃ is selected from the group consisting of: -Z-Y—R₄,Z-Y—X—Y—R₄, -Z-Y—X—Y—X—Y—R₄, -Z-R₅, -Z-Het, -Z-Het′-R₄, and-Z-Het′-Y—R₄; R is selected from the group consisting of alkyl, alkoxy,hydroxy, halogen, and trifluoromethyl; G is selected from the groupconsisting of: —C(O)—R′, α-aminoacyl, α-aminoacyl-α-aminoacyl,—C(O)—O—R′, —C(O)—N(R′″)R′, —C(═NY₁)—R′, —CH(OH)—C(O)—OY₁, —CH(OC₁₋₄alkyl)Y₀, —CH₂Y₂, and —CH(CH₃)Y₂; R′ and R′″ are independently selectedfrom the group consisting of C₁₀ alkyl, C₃₋₇ cycloalkyl, phenyl, andbenzyl, each of which may be unsubstituted or substituted by one or moresubstituents independently selected from the group consisting ofhalogen, hydroxy, nitro, cyano, carboxy, C₁₋₆ alkyl, C₁₋₄ alkoxy, aryl,heteroaryl, aryl-C₁₋₄ alkylenyl, heteroaryl-C₁₋₄ alkylenyl, halo-C₁₋₄alkylenyl, halo-C₁₋₄ alkoxy, —O—C(O)—CH₃, —C(O)—O—CH₃, —C(O)—NH₂,—O—CH₂—C(O)—NH₂, —NH₂, and —S(O)₂—NH₂, with the proviso that R′″ canalso be hydrogen; α-aminoacyl is an α-aminoacyl group derived from anamino acid selected from the group consisting of racemic, D-, andL-amino acids; Y₁ is selected from the group consisting of hydrogen,C₁₋₆ alkyl, and benzyl; Y₀ is selected from the group consisting of C₁₋₆alkyl, carboxy-C₁₋₆ alkylenyl, amino-C₁₋₄ alkylenyl, mono-N—C₁₋₆alkylamino-C₁₋₄alkylenyl, and di-N,N—C₁₋₆ alkylamino-C₁₋₄ alkylenyl; Y₂is selected from the group consisting of mono-N—C₁₋₆ alkylamino,di-N,N—C₁₋₆ alkylamino, morpholin-4-yl, piperidin-1-yl, pyrrolidin-1-yl,and 4-C₁₋₄ alkylpiperazin-1-yl; R₂ is selected from the group consistingof: —R₄, —X—R₄, —X—Y′—R₄, and —X—R₅′; Z is selected from the groupconsisting of alkylene, alkenylene, and alkynylene, wherein alkylene,alkenylene, and alkynylene can be optionally interrupted with one ormore —O— groups; Y is selected from the group consisting of: —S(O)₀₋₂—,—S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—, —O—C(R₆)—, —O—C(O)—O—, —N(R₈)-Q-,—C(R₆)—N(R₈)—, —O—C(R₆)—N(R₈)—, —C(R₆)—N(OR₉)—, —O—N(R₈)-Q-,—O—N═C(R₄)—, —C(═N—O—R₈)—, —CH(—N(—O—R₈)-Q-R₄)—,

Het is heterocyclyl which can be unsubstituted or substituted by one ormore substituents independently selected from the group consisting ofalkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy,hydroxyalkyl, cyano, hydroxyalkyleneoxyalkylenyl, amino, alkylamino,dialkylamino, and oxo; Het′ is heterocyclylene which can beunsubstituted or substituted by one or more substituents independentlyselected from the group consisting of alkyl, alkoxy, haloalkyl,haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, amino,alkylamino, dialkylamino, and oxo; X is selected from the groupconsisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene,and heterocyclylene wherein the alkylene, alkenylene, and alkynylenegroups can be optionally interrupted or terminated with arylene,heteroarylene, or heterocyclylene, and optionally interrupted by one ormore —O— groups; Y′ is selected from the group consisting of: —O—,—S(O)₀₋₂—, —S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—, —O—C(R₆)—, —O—C(O)—O—,—N(R₈)-Q-, —C(R₆)—N(R₈)—, —O—C(R₆)—N(R₈)—, —C(R₆)—N(OR₉)—,

R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo; R₅ is selected from the group consisting of:

R₅′ is selected from the group consisting of:

R₆ is selected from the group consisting of ═O and ═S; R₇ is C₂₋₇alkylene; R₈ is selected from the group consisting of hydrogen, alkyl,hydroxyalkylenyl, alkoxyalkylenyl, arylalkylenyl, andheteroarylalkylenyl; R₉ is selected from the group consisting ofhydrogen and alkyl; R₁₀ is C₃₋₈ alkylene; A is selected from the groupconsisting of —O—, —CH₂—, —C(O)—, —S(O)₀₋₂—, and —N(R₄)—; A′ is selectedfrom the group consisting of —O—, —S(O)₀₋₂—, —N(-Q-R₄)—, and —CH₂—; Q isselected from the group consisting of a bond, —C(R₆)—, —C(R₆)—C(R₆)—,—S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, and —C(R₆)—N(OR₉)—;V is selected from the group consisting of —C(R₆)—, —O—C(R₆)—,—N(R₈)—C(R₆)—, and —S(O)₂—; W is selected from the group consisting of abond, —C(O)—, and —S(O)₂—; and a and b are independently integers from 1to 6 with the proviso that a+b is ≦7; with the proviso that Z can alsobe a bond when: R₃ is -Z-Het, -Z-Het′-R₄, or -Z-Het′-Y—R₄, and Z isattached to an atom other than N in Het or Het′; or R₃ is -Z-Y—R₄,-Z-Y—X—Y—R₄, or -Z-Y—X—Y—X—Y—R₄, and the Y group bonded to Z is —S(O)₂—,—S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—, —C(R₆)—N(R₈),

 wherein V is —C(R₆)— or —S(O)₂—, or

R₃ is -Z-R₅, and R₅ is

 wherein V is —C(R₆)— or —S(O)₂—, or

and with the further proviso that Y can also be —O— when: Y is bonded toR₄, and R₄ is selected from the group consisting of hydrogen, aryl, andheteroaryl, wherein aryl and heteroaryl can be unsubstituted orsubstituted by one or more substituents; or Y is bonded to Z and X, andX is arylene or heteroarylene; or a pharmaceutically acceptable saltthereof.
 4. (canceled)
 5. A compound of claim 1, wherein Formula I isFormula II:

wherein: R₃ is selected from the group consisting of: -Z-Y—R₄,-Z-Y—X—Y—R₄, -Z-Y—X—Y—X—Y—R₄, -Z-R₅, -Z-Het, -Z-Het′-R₄, and-Z-Het′-Y—R₄; R is selected from the group consisting of alkyl, alkoxy,hydroxy, halogen, and trifluoromethyl; n is 0 or 1; R₂ is selected fromthe group consisting of: —R₄, —X—R₄, —X—Y′—R₄, and —X—R₅′; Z is selectedfrom the group consisting of alkylene, alkenylene, and alkynylene,wherein alkylene, alkenylene, and alkynylene can be optionallyinterrupted with one or more —O— groups; Y is selected from the groupconsisting of: —S(O)₀₋₂—, —S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—, —O—C(R₆)—,—O—C(O)—O—, —N(R₈)-Q-, —C(R₆)—N(R₈)—, —O—C(R₆)—N(R₈)—, —C(R₆)—N(OR₉)—,—O—N(R₈)-Q-, —O—N═C(R₄)—, —C(═N—O—R₈)—, —CH(—N(—O—R₈)-Q-R₄)—,

Het is heterocyclyl which can be unsubstituted or substituted by one ormore substituents independently selected from the group consisting ofalkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy,hydroxyalkyl, cyano, hydroxyalkyleneoxyalkylenyl, amino, alkylamino,dialkylamino, and oxo; Het′ is heterocyclylene which can beunsubstituted or substituted by one or more substituents independentlyselected from the group consisting of alkyl, alkoxy, haloalkyl,haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, amino,alkylamino, dialkylamino, and oxo; X is selected from the groupconsisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene,and heterocyclylene wherein the alkylene, alkenylene, and alkynylenegroups can be optionally interrupted or terminated with arylene,heteroarylene, or heterocyclylene, and optionally interrupted by one ormore —O— groups; Y′ is selected from the group consisting of: —O—,—S(O)₀₋₂—, —S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—, —O—C(R₆)—, —O—C(O)—O—,—N(R₈)-Q-, —C(R₆)—N(R₈)—, —O—C(R₆)—N(R₈)—, —C(R₆)—N(OR₉)—,

R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo; R₅ is selected from the group consisting of:

R₅′ is selected from the group consisting of:

R₅′ is selected from the group consisting of ═O and ═S; R₇ is C₂₋₇alkylene; R₈ is selected from the group consisting of hydrogen, alkyl,hydroxyalkylenyl, alkoxyalkylenyl, arylalkylenyl, andheteroarylalkylenyl; R₉ is selected from the group consisting ofhydrogen and alkyl; R₁₀ is C₃₋₈ alkylene; A is selected from the groupconsisting of —O—, —CH₂—, —C(O)—, —S(O)₀₋₂—, and —N(R₄)—; A′ is selectedfrom the group consisting of —O—, —S(O)₀₋₂—, —N(-Q-R₄)—, and —CH₂—; Q isselected from the group consisting of a bond, —C(R₆)—, —C(R₆)—C(R₆)—,—S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, and —C(R₆)—N(OR₉)—;V is selected from the group consisting of —C(R₆)—, —O—C(R₆)—,—N(R₈)—C(R₆)—, and —S(O)₂—; W is selected from the group consisting of abond, —C(O)—, and —S(O)₂—; and a and b are independently integers from 1to 6 with the proviso that a+b is ≦7; with the proviso that Z can alsobe a bond when: R₃ is -Z-Het, -Z-Het′-R₄, or -Z-Het′-Y—R₄, and Z isattached to an atom other than N in Het or Het′; or R₃ is -Z-Y—R₄,-Z-Y—X—Y—R₄, or -Z-Y—X—Y—X—Y—R₄, and the Y group bonded to Z is —S(O)₂—,—S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—, —C(R₆)—N(R₈)—,

 wherein V is —C(R₆)— or —S(O)₂—, or

 or R₃ is -Z-R₅, and R₅ is

 wherein V is —C(R₆)— or —S(O)₂—, or

 and with the further proviso that Y can also be —O— when: Y is bondedto R₄, and R₄ is selected from the group consisting of hydrogen, aryl,and heteroaryl, wherein aryl and heteroaryl can be unsubstituted orsubstituted by one or more substituents; or Y is bonded to Z and X, andX is arylene or heteroarylene; or a pharmaceutically acceptable saltthereof.
 6. The compound or salt of claim 5 wherein n is
 0. 7-8.(canceled)
 9. The compound or salt of claim 5 wherein R₃ is -Z-Y—R₄ or-Z-Y—X—Y—R₄.
 10. The compound or salt of claim 9 wherein Y is —N(R₈)-Q-,

or —C(O)—; wherein Q is selected from the group consisting of a bond,—C(O)—, —C(O)—O—, —S(O)₂—, —C(R₆)—N(R₈)—, and —S(O)₂—N(R₈)—; R₆ isselected from the group consisting of ═O or —S; R₇ is C₂₋₃ alkylene; R₈is selected from the group consisting of hydrogen, C₁₋₄ alkyl, and C₁₋₄alkoxyC₁₋₄ alkylenyl; R₁₀ is C₃₋₆ alkylene; and R₄ is selected from thegroup consisting of alkyl, aryl, arylalkylenyl, alkylheteroarylenyl,heteroarylalkylenyl, heteroaryl, and heterocyclyl; wherein alkyl isunsubstituted or substituted by one or more substituents selected fromthe group consisting of hydroxy, alkoxy, halogen, and aryl; whereinaryl, heteroaryl, and arylalkylenyl are unsubstituted or substituted byone or more substituents selected from the group consisting of alkyl,halogen, cyano, dialkylamino, and alkoxy; and wherein heterocyclyl isunsubstituted or substituted by one or more alkyl substituents. 11-18.(canceled)
 19. The compound or salt of claim 5 wherein: R₃ is -Z-Y—R₄,wherein Y is —O— and R₄ is phenyl that is unsubstituted or substitutedby one or more substituents selected from the group consisting of alkyl,halogen, cyano, alkoxy, nitro, and haloalkyl; or R₃ is -Z-Y—X—Y_(c)—R₄,wherein Y is —O—, X is phenylene, and Y_(c)—R₄ is selected from thegroup consisting of —C(O)-alkyl, —C(O)—O-alkyl, —S-alkyl,—NH—C(O)-alkyl, —C(O)—NH₂, and —S(O)₂—NH₂.
 20. The compound or salt ofclaim 5 wherein R₃ is -Z-R₅. 21-22. (canceled)
 23. The compound or saltof claim 5 wherein R₃ is -Z-Het or -Z-Het′-R₄. 24-27. (canceled)
 28. Thecompound or salt of claim 5 wherein R₃ is -Z-Het′-Y—R₄. 29-30.(canceled)
 31. The compound or salt of claim 5 wherein Z is alkyleneoptionally interrupted with one or more —O— groups.
 32. (canceled) 33.The compound or salt of claim 5 wherein Z is a bond.
 34. The compound orsalt of claim 5 wherein —O—R₃ is at the 7-position.
 35. A compound ofthe Formula X:

wherein: R is selected from the group consisting of alkyl, alkoxy,hydroxy, halogen, and trifluoromethyl; n is 0 or 1; R₂ is selected fromthe group consisting of: —R₄, —X—R₄, —X—Y′—R₄, and —X—R₅′; Z is selectedfrom the group consisting of alkylene, alkenylene, and alkynylene,wherein alkylene, alkenylene, and alkynylene can be optionallyinterrupted with one or more —O— groups; X is selected from the groupconsisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene,and heterocyclylene wherein the alkylene, alkenylene, and alkynylenegroups can be optionally interrupted or terminated with arylene,heteroarylene, or heterocyclylene, and optionally interrupted by one ormore —O— groups; Y′ is selected from the group consisting of: —O—,—S(O)₀₋₂—, —S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—, —O—C(R₆)—, —O—C(O)—O—,—N(R₈)-Q-, —C(R₆)—N(R₈)—, —O—C(R₆)—N(R₈)—, —C(R₆)—N(OR₉)—,

R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo; R₅′ is selected from the group consisting of:

R₆ is selected from the group consisting of ═O and ═S; R₇ is C₂₋₇alkylene; R₈ is selected from the group consisting of hydrogen, alkyl,hydroxyalkylenyl, alkoxyalkylenyl, arylalkylenyl, andheteroarylalkylenyl; R₉ is selected from the group consisting ofhydrogen and alkyl; R₁₀ is C₃₋₈ alkylene; A is selected from the groupconsisting of —O—, —CH₂—, —C(O)—, —S(O)₀₋₂—, and —N(R₄)—; Q is selectedfrom the group consisting of a bond, —C(R₆)—, —C(R₆)—C(R₆)—, —S(O)₂—,—C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, and —C(R₆)—N(OR₉)—; V isselected from the group consisting of-C(R₆)—, —O—C(R₆)—, —N(R₈)—C(R₆)—,and —S(O)₂—; W is selected from the group consisting of a bond, —C(O)—,and —S(O)₂—; and a and b are independently integers from 1 to 6 with theproviso that a+b is ≦7; or a pharmaceutically acceptable salt thereof.36. (canceled)
 37. A pharmaceutical composition comprising atherapeutically effective amount of a compound or salt of claim 1 and apharmaceutically acceptable carrier.
 38. A method of inducing cytokinebiosynthesis in an animal comprising administering an effective amountof a compound or salt of claim 1 to the animal.
 39. A method of treatinga viral disease in an animal in need thereof comprising administering atherapeutically effective amount of a compound or salt of claim
 1. 40. Amethod of treating a neoplastic disease in an animal in need thereofcomprising administering a therapeutically effective amount of acompound or salt of claim
 1. 41. A compound of the Formula XII:

wherein: R₃ is selected from the group consisting of: -Z-Y—R₄,-Z-Y—X—Y—R₄, -Z-Y—X—Y—X—Y—R₄, -Z-R₅, -Z-Het, -Z-Het′-R₄, and-Z-Het′-Y—R₄; R is selected from the group consisting of alkyl, alkoxy,hydroxy, halogen, and trifluoromethyl; n is 0 or 1; R₂ is selected fromthe group consisting of: —R₄, —X—R₄, —X—Y′—R₄, and —X—R₅′; Z is selectedfrom the group consisting of alkylene, alkenylene, and alkynylene,wherein alkylene, alkenylene, and alkynylene can be optionallyinterrupted with one or more —O— groups; Y is selected from the groupconsisting of: —S(O)₀₋₂—, —S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—, —O—C(R₆)—,—O—C(O)—O—, —N(R₈)-Q-, —C(R₆)—N(R₈)—, —O—C(R₆)—N(R₈)—, —C(R₆)—N(OR₉)—,—O—N(R₈)-Q-, —O—N═C(R₄)—, —C(═N—O—R₈)—, —CH(—N(—O—R₈)-Q-R₄)—,

Het is heterocyclyl which can be unsubstituted or substituted by one ormore substituents independently selected from the group consisting ofalkyl, alkoxy, haloalkyl, haloalkoxy, halogen, nitro, hydroxy,hydroxyalkyl, cyano, hydroxyalkyleneoxyalkylenyl, amino, alkylamino,dialkylamino, and oxo; Het′ is heterocyclylene which can beunsubstituted or substituted by one or more substituents independentlyselected from the group consisting of alkyl, alkoxy, haloalkyl,haloalkoxy, halogen, nitro, hydroxy, hydroxyalkyl, cyano, amino,alkylamino, dialkylamino, and oxo; X is selected from the groupconsisting of alkylene, alkenylene, alkynylene, arylene, heteroarylene,and heterocyclylene wherein the alkylene, alkenylene, and alkynylenegroups can be optionally interrupted or terminated with arylene,heteroarylene, or heterocyclylene, and optionally interrupted by one ormore —O— groups; Y′ is selected from the group consisting of: —O—,—S(O)₀₋₂—, —S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—, —O—C(R₆)—, —O—C(O)—O—,—N(R₈)-Q-, —C(R₆)—N(R₈)—, —O—C(R₆)—N(R₈)—, —C(R₆)—N(OR₉)—,

R₄ is selected from the group consisting of hydrogen, alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl wherein the alkyl, alkenyl,alkynyl, aryl, arylalkylenyl, aryloxyalkylenyl, alkylarylenyl,heteroaryl, heteroarylalkylenyl, heteroaryloxyalkylenyl,alkylheteroarylenyl, and heterocyclyl groups can be unsubstituted orsubstituted by one or more substituents independently selected from thegroup consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy,halogen, nitro, hydroxy, mercapto, cyano, aryl, aryloxy,arylalkyleneoxy, heteroaryl, heteroaryloxy, heteroarylalkyleneoxy,heterocyclyl, amino, alkylamino, dialkylamino,(dialkylamino)alkyleneoxy, and in the case of alkyl, alkenyl, alkynyl,and heterocyclyl, oxo; R₅ is selected from the group consisting of:

R₅′ is selected from the group consisting of:

R₆ is selected from the group consisting of ═O and ═S; R₇ is C₂₋₇alkylene; R₈ is selected from the group consisting of hydrogen, alkyl,hydroxyalkylenyl, alkoxyalkylenyl, arylalkylenyl, andheteroarylalkylenyl; R₉ is selected from the group consisting ofhydrogen and alkyl; R₁₀ is C₃₋₈ alkylene; A is selected from the groupconsisting of —O—, —CH₂—, —C(O)—, —S(O)₀₋₂—, and —N(R₄)—; A′ is selectedfrom the group consisting of —O—, —S(O)₀₋₂—, —N(-Q-R₄)—, and —CH₂—; Q isselected from the group consisting of a bond, —C(R₆)—, —C(R₆)—C(R₆)—,—S(O)₂—, —C(R₆)—N(R₈)—W—, —S(O)₂—N(R₈)—, —C(R₆)—O—, and —C(R₆)—N(OR₉)—;V is selected from the group consisting of-C(R₆)—, —O—C(R₆)—,—N(R₈)—C(R₆)—, and —S(O)₂—; W is selected from the group consisting of abond, —C(O)—, and —S(O)₂—; and a and b are independently integers from 1to 6 with the proviso that a+b is ≦7; with the proviso that Z can alsobe a bond when: R₃ is -Z-Het, -Z-Het′-R₄, or -Z-Het′-Y—R₄, and Z isattached to an atom other than N in Het or Het′; or R₃ is -Z-Y—R₄,-Z-Y—X—Y—R₄, or -Z-Y—X—Y—X—Y—R₄, and the Y group bonded to Z is —S(O)₂—,—S(O)₂—N(R₈)—, —C(R₆)—, —C(R₆)—O—, —C(R₆)—N(R₈)—,

 wherein V is —C(R₆)— or —S(O)₂—, or

 or R₃ is -Z-R₅, and R₅ is

 wherein V is —C(R₆)— or —S(O)₂—, or

 and with the further proviso that Y can also be —O— when: Y is bondedto R₄, and R₄ is selected from the group consisting of hydrogen, aryl,and heteroaryl, wherein aryl and heteroaryl can be unsubstituted orsubstituted by one or more substituents; or Y is bonded to Z and X, andX is arylene or heteroarylene; or a pharmaceutically acceptable saltthereof.